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Eight Subcellular Pathologies driving Chronic Metabolic Diseases – Methods for Mapping Bioelectronic Adjustable Measurements as potential new Therapeutics: Impact on Pharmaceuticals in Use

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Eight Subcellular Pathologies driving Chronic Metabolic Diseases – Methods for Mapping Bioelectronic Adjustable Measurements as potential new Therapeutics: Impact on Pharmaceuticals in Use

Curators:

• Cardiovascular Expertise – Dr. Justin D. Pearlman, MD, PhD, FACC
• Pharmacology and Oncology Expertise – Dr. Stephen J. Williams, PhD
• Principal Investigator, initiator of the project – Aviva Lev-Ari, PhD, RN

 

THE VOICE of Aviva Lev-Ari, PhD, RN

In this curation we wish to present two breaking through goals:

Goal 1:

Exposition of a new direction of research leading to a more comprehensive understanding of Metabolic Dysfunctional Diseases that are implicated in effecting the emergence of the two leading causes of human mortality in the World in 2023: (a) Cardiovascular Diseases, and (b) Cancer

Goal 2:

Development of Methods for Mapping Bioelectronic Adjustable Measurements as potential new Therapeutics for these eight subcellular causes of chronic metabolic diseases. It is anticipated that it will have a potential impact on the future of Pharmaceuticals to be used, a change from the present time current treatment protocols for Metabolic Dysfunctional Diseases.

According to Dr. Robert Lustig, M.D, an American pediatric endocrinologist. He is Professor emeritus of Pediatrics in the Division of Endocrinology at the University of California, San Francisco, where he specialized in neuroendocrinology and childhood obesity, there are eight subcellular pathologies that drive chronic metabolic diseases.

These eight subcellular pathologies can’t be measured at present time.

In this curation we will attempt to explore methods of measurement for each of these eight pathologies by harnessing the promise of the emerging field known as Bioelectronics.

Unmeasurable eight subcellular pathologies that drive chronic metabolic diseases

1. Glycation
2. Oxidative Stress
3. Mitochondrial dysfunction [beta-oxidation Ac CoA malonyl fatty acid]
4. Insulin resistance/sensitive [more important than BMI], known as a driver to cancer development
5. Membrane instability
6. Inflammation in the gut [mucin layer and tight junctions]
7. Epigenetics/Methylation
8. Autophagy [AMPKbeta1 improvement in health span]

Diseases that are not Diseases: no drugs for them, only diet modification will help

Image source

Robert Lustig, M.D. on the Subcellular Processes That Belie Chronic Disease

https://www.youtube.com/watch?v=Ee_uoxuQo0I

 

Exercise will not undo Unhealthy Diet

Image source

Robert Lustig, M.D. on the Subcellular Processes That Belie Chronic Disease

https://www.youtube.com/watch?v=Ee_uoxuQo0I

 

These eight Subcellular Pathologies driving Chronic Metabolic Diseases are becoming our focus for exploration of the promise of Bioelectronics for two pursuits:

1. Will Bioelectronics be deemed helpful in measurement of each of the eight pathological processes that underlie and that drive the chronic metabolic syndrome(s) and disease(s)?
2. IF we will be able to suggest new measurements to currently unmeasurable health harming processes THEN we will attempt to conceptualize new therapeutic targets and new modalities for therapeutics delivery – WE ARE HOPEFUL

In the Bioelecronics domain we are inspired by the work of the following three research sources:

1. Biological and Biomedical Electrical Engineering (B2E2) at Cornell University, School of Engineering https://www.engineering.cornell.edu/bio-electrical-engineering-0
2. Bioelectronics Group at MIT https://bioelectronics.mit.edu/
3. The work of Michael Levin @Tufts, The Levin Lab

Michael Levin is an American developmental and synthetic biologist at Tufts University, where he is the Vannevar Bush Distinguished Professor. Levin is a director of the Allen Discovery Center at Tufts University and Tufts Center for Regenerative and Developmental Biology. Wikipedia

Born: 1969 (age 54 years), Moscow, Russia

Education: Harvard University (1992–1996), Tufts University (1988–1992)

Affiliation: University of Cape Town

Research interests: Allergy, Immunology, Cross Cultural Communication

Awards: Cozzarelli prize (2020)

Doctoral advisor: Clifford Tabin

Fields: Developmental biology, synthetic biology

SOURCE

https://www.google.com/search?q=Michael+Levin+%40Tufts&oq=Michael+Levin+%40Tufts&aqs=chrome..69i57j69i58.894128314j0j15&sourceid=chrome&ie=UTF-8

Most recent 20 Publications by Michael Levin, PhD

SOURCE

https://facultyprofiles.tufts.edu/michael-levin-1/publications

SCHOLARLY ARTICLE

The nonlinearity of regulation in biological networks

1 Dec 2023npj Systems Biology and Applications9(1)

Co-authorsManicka S, Johnson K, Levin M…1 more

VIEW PDF10.1038/S41540-023-00273-W

3

SCHOLARLY ARTICLE

Toward an ethics of autopoietic technology: Stress, care, and intelligence

1 Sep 2023BioSystems231

Co-authorsWitkowski O, Doctor T, Solomonova E…2 more

VIEW PDF10.1016/J.BIOSYSTEMS.2023.104964

SCHOLARLY ARTICLE

Closing the Loop on Morphogenesis: A Mathematical Model of Morphogenesis by Closed-Loop Reaction-Diffusion

14 Aug 2023Frontiers in Cell and Developmental Biology11:1087650

Co-authorsGrodstein J, McMillen P, Levin M

VIEW PDF10.3389/FCELL.2023.1087650

SCHOLARLY ARTICLE

Correcting instructive electric potential patterns in multicellular systems: External actions and endogenous processes.

30 Jul 2023Biochim Biophys Acta Gen Subj1867(10):130440

Co-authorsCervera J, Levin M, Mafe S

VIEW MORE INFO10.1016/J.BBAGEN.2023.130440

SCHOLARLY ARTICLE

Regulative development as a model for origin of life and artificial life studies

1 Jul 2023BioSystems229

Co-authorsFields C, Levin M

10.1016/J.BIOSYSTEMS.2023.104927

1

SCHOLARLY ARTICLE

The Yin and Yang of Breast Cancer: Ion Channels as Determinants of Left–Right Functional Differences

1 Jul 2023International Journal of Molecular Sciences24(13)

Co-authorsMasuelli S, Real S, McMillen P…3 more

VIEW PDF10.3390/IJMS241311121

SCHOLARLY ARTICLE

Bioelectricidad en agregados multicelulares de células no excitables- modelos biofísicos

Jun 2023Revista Española de Física32(2)

Co-authorsCervera J, Levin M, Mafé S

SCHOLARLY ARTICLE

Bioelectricity: A Multifaceted Discipline, and a Multifaceted Issue!

1 Jun 2023Bioelectricity5(2):75

Co-authorsDjamgoz MBA, Levin M

10.1089/BIOE.2023.0022.EDITORIAL

SCHOLARLY ARTICLE

Control Flow in Active Inference Systems – Part I: Classical and Quantum Formulations of Active Inference

1 Jun 2023IEEE Transactions on Molecular, Biological, and Multi-Scale Communications9(2):235-245

Co-authorsFields C, Fabrocini F, Friston K…4 more

10.1109/TMBMC.2023.3272150

2

SCHOLARLY ARTICLE

Control Flow in Active Inference Systems – Part II: Tensor Networks as General Models of Control Flow

1 Jun 2023IEEE Transactions on Molecular, Biological, and Multi-Scale Communications9(2):246-256

Co-authorsFields C, Fabrocini F, Friston K…4 more

10.1109/TMBMC.2023.3272158

2

SCHOLARLY ARTICLE

Darwin’s agential materials: evolutionary implications of multiscale competency in developmental biology

1 Jun 2023Cellular and Molecular Life Sciences80(6)

Co-authorsLevin M

VIEW PDF10.1007/S00018-023-04790-Z

1

SCHOLARLY ARTICLE

Morphoceuticals: Perspectives for discovery of drugs targeting anatomical control mechanisms in regenerative medicine, cancer and aging

1 Jun 2023Drug Discovery Today28(6)

Co-authorsPio-Lopez L, Levin M

VIEW PDF10.1016/J.DRUDIS.2023.103585

1

SCHOLARLY ARTICLE

Morphoceuticals: Perspectives for discovery of drugs targeting anatomical control mechanisms in regenerative medicine, cancer and aging

Jun 2023DRUG DISCOVERY TODAY28(6):1-13

Co-authorsPio-Lopez L, Levin M

VIEW MORE INFO10.1016/J.DRUDIS.2023.103585THIS

SCHOLARLY ARTICLE

Cellular signaling pathways as plastic, proto-cognitive systems: Implications for biomedicine

12 May 2023Patterns4(5)

Co-authorsMathews J, Chang A, Devlin L…1 more

VIEW PDF10.1016/J.PATTER.2023.100737

3

SCHOLARLY ARTICLE

Making and breaking symmetries in mind and life

14 Apr 2023Interface Focus13(3)

Co-authorsSafron A, Sakthivadivel DAR, Sheikhbahaee Z…3 more

VIEW PDF10.1098/RSFS.2023.0015

SCHOLARLY ARTICLE

The scaling of goals from cellular to anatomical homeostasis: an evolutionary simulation, experiment and analysis

14 Apr 2023Interface Focus13(3)

Co-authorsPio-Lopez L, Bischof J, LaPalme JV…1 more

VIEW PDF10.1098/RSFS.2022.0072

1

SCHOLARLY ARTICLE

The collective intelligence of evolution and development

Apr 2023Collective Intelligence2(2):263391372311683SAGE Publications

Co-authorsWatson R, Levin M

VIEW PDF10.1177/26339137231168355

SCHOLARLY ARTICLE

Bioelectricity of non-excitable cells and multicellular pattern memories: Biophysical modeling

13 Mar 2023Physics Reports1004:1-31

Co-authorsCervera J, Levin M, Mafe S

10.1016/J.PHYSREP.2022.12.003

2

SCHOLARLY ARTICLE

There’s Plenty of Room Right Here: Biological Systems as Evolved, Overloaded, Multi-Scale Machines

1 Mar 2023Biomimetics8(1)

Co-authorsBongard J, Levin M

VIEW PDF10.3390/BIOMIMETICS8010110

4

SCHOLARLY ARTICLE

Transplantation of fragments from different planaria: A bioelectrical model for head regeneration

7 Feb 2023Journal of Theoretical Biology558

Co-authorsCervera J, Manzanares JA, Levin M…1 more

VIEW PDF10.1016/J.JTBI.2022.111356

SCHOLARLY ARTICLE

Bioelectric networks: the cognitive glue enabling evolutionary scaling from physiology to mind

1 Jan 2023Animal Cognition

Co-authorsLevin M

VIEW PDF10.1007/S10071-023-01780-3

2

SCHOLARLY ARTICLE

Biological Robots: Perspectives on an Emerging Interdisciplinary Field

1 Jan 2023Soft Robotics

Co-authorsBlackiston D, Kriegman S, Bongard J…1 more

10.1089/SORO.2022.0142

1

SCHOLARLY ARTICLE

Cellular Competency during Development Alters Evolutionary Dynamics in an Artificial Embryogeny Model

1 Jan 2023Entropy25(1)

Co-authorsShreesha L, Levin M

VIEW PDF10.3390/E25010131

5

SCHOLARLY ARTICLE

Endless forms most beautiful 2.0: teleonomy and the bioengineering of chimaeric and synthetic organisms (July, blac073, 2022)

1 Jan 2023BIOLOGICAL JOURNAL OF THE LINNEAN SOCIETY138(1):141

Co-authorsClawson WP, Levin M

VIEW PDFVIEW MORE INFO10.1093/BIOLINNEAN/BLAC116

SCHOLARLY ARTICLE

Future medicine: from molecular pathways to the collective intelligence of the body

1 Jan 2023Trends in Molecular Medicine

Co-authorsLagasse E, Levin M

10.1016/J.MOLMED.2023.06.007

THE VOICE of Dr. Justin D. Pearlman, MD, PhD, FACC

PENDING

THE VOICE of  Stephen J. Williams, PhD

Ten TakeAway Points of Dr. Lustig’s talk on role of diet on the incidence of Type II Diabetes

 

1. 25% of US children have fatty liver
2. Type II diabetes can be manifested from fatty live with 151 million  people worldwide affected moving up to 568 million in 7 years
3. A common myth is diabetes due to overweight condition driving the metabolic disease
4. There is a trend of ‘lean’ diabetes or diabetes in lean people, therefore body mass index not a reliable biomarker for risk for diabetes
5. Thirty percent of ‘obese’ people just have high subcutaneous fat.  the visceral fat is more problematic
6. there are people who are ‘fat’ but insulin sensitive while have growth hormone receptor defects.  Points to other issues related to metabolic state other than insulin and potentially the insulin like growth factors
7. At any BMI some patients are insulin sensitive while some resistant
8. Visceral fat accumulation may be more due to chronic stress condition
9. Fructose can decrease liver mitochondrial function
10. A methionine and choline deficient diet can lead to rapid NASH development

 

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Endoglin Protein Interactome Profiling Identifies TRIM21 and Galectin-3 as New Binding Partners

Posted in Biological Networks, Cardiomyopathy, Cardiovascular and Vascular Systems, Cardiovascular Research, Cell Biology, Cell Biology, Signaling & Cell Circuits, Disease Biology, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Enzymes and isoenzymes, Gene Regulation, Glycobiology: Biopharmaceutical Production, Proteins, Proteomics, Ubiquitin, Vascular Diseases, tagged E3 ubiquitin ligase, endoglin, galectin, galectin-3, microarray, protein complex, protein-protein interaction, Proteomics, proteosome, ring finger, TRIM21, Ubiquitin on October 11, 2022| Leave a Comment »

Endoglin Protein Interactome Profiling Identifies TRIM21 and Galectin-3 as New Binding Partners

Curator: Stephen J. Williams, Ph.D.

First please see the summary of LPBI efforts into development of inhibitors of Galectin-3 for cancer therapeutics

Mission 4: Use of Systems Biology for Design of inhibitor of Galectins as Cancer Therapeutic – Strategy and Software

The following paper in Cells describes the discovery of protein interactors of endoglin, which is recruited to membranes at the TGF-β receptor complex upon TGF-β signaling. Interesting a carbohydrate binding protein, galectin-3, and an E3-ligase, TRIM21, were found to be unique interactors within this complex.

Gallardo-Vara E, Ruiz-Llorente L, Casado-Vela J, Ruiz-Rodríguez MJ, López-Andrés N, Pattnaik AK, Quintanilla M, Bernabeu C. Endoglin Protein Interactome Profiling Identifies TRIM21 and Galectin-3 as New Binding Partners. Cells. 2019 Sep 13;8(9):1082. doi: 10.3390/cells8091082. PMID: 31540324; PMCID: PMC6769930.

Abstract

Endoglin is a 180-kDa glycoprotein receptor primarily expressed by the vascular endothelium and involved in cardiovascular disease and cancer. Heterozygous mutations in the endoglin gene (ENG) cause hereditary hemorrhagic telangiectasia type 1, a vascular disease that presents with nasal and gastrointestinal bleeding, skin and mucosa telangiectases, and arteriovenous malformations in internal organs. A circulating form of endoglin (alias soluble endoglin, sEng), proteolytically released from the membrane-bound protein, has been observed in several inflammation-related pathological conditions and appears to contribute to endothelial dysfunction and cancer development through unknown mechanisms. Membrane-bound endoglin is an auxiliary component of the TGF-β receptor complex and the extracellular region of endoglin has been shown to interact with types I and II TGF-β receptors, as well as with BMP9 and BMP10 ligands, both members of the TGF-β family. To search for novel protein interactors, we screened a microarray containing over 9000 unique human proteins using recombinant sEng as bait. We find that sEng binds with high affinity, at least, to 22 new proteins. Among these, we validated the interaction of endoglin with galectin-3, a secreted member of the lectin family with capacity to bind membrane glycoproteins, and with tripartite motif-containing protein 21 (TRIM21), an E3 ubiquitin-protein ligase. Using human endothelial cells and Chinese hamster ovary cells, we showed that endoglin co-immunoprecipitates and co-localizes with galectin-3 or TRIM21. These results open new research avenues on endoglin function and regulation.

Source: https://www.mdpi.com/2073-4409/8/9/1082/htm

Endoglin is an auxiliary TGF-β co-receptor predominantly expressed in endothelial cells, which is involved in vascular development, repair, homeostasis, and disease [1,2,3,4]. Heterozygous mutations in the human ENDOGLIN gene (ENG) cause hereditary hemorrhagic telangiectasia (HHT) type 1, a vascular disease associated with nasal and gastrointestinal bleeds, telangiectases on skin and mucosa and arteriovenous malformations in the lung, liver, and brain [4,5,6]. The key role of endoglin in the vasculature is also illustrated by the fact that endoglin-KO mice die in utero due to defects in the vascular system [7]. Endoglin expression is markedly upregulated in proliferating endothelial cells involved in active angiogenesis, including the solid tumor neovasculature [8,9]. For this reason, endoglin has become a promising target for the antiangiogenic treatment of cancer [10,11,12]. Endoglin is also expressed in cancer cells where it can behave as both a tumor suppressor in prostate, breast, esophageal, and skin carcinomas [13,14,15,16] and a promoter of malignancy in melanoma and Ewing’s sarcoma [17]. Ectodomain shedding of membrane-bound endoglin may lead to a circulating form of the protein, also known as soluble endoglin (sEng) [18,19,20]. Increased levels of sEng have been found in several vascular-related pathologies, including preeclampsia, a disease of high prevalence in pregnant women which, if left untreated, can lead to serious and even fatal complications for both mother and baby [2,18,19,21]. Interestingly, several lines of evidence support a pathogenic role of sEng in the vascular system, including endothelial dysfunction, antiangiogenic activity, increased vascular permeability, inflammation-associated leukocyte adhesion and transmigration, and hypertension [18,22,23,24,25,26,27]. Because of its key role in vascular pathology, a large number of studies have addressed the structure and function of endoglin at the molecular level, in order to better understand its mechanism of action.

 Galectin-3 Interacts with Endoglin in Cells

Galectin-3 is a secreted member of the lectin family with the capacity to bind membrane glycoproteins like endoglin and is involved in the pathogenesis of many human diseases [52]. We confirmed the protein screen data for galectin-3, as evidenced by two-way co-immunoprecipitation of endoglin and galectin-3 upon co-transfection in CHO-K1 cells. As shown in Figure 1A, galectin-3 and endoglin were efficiently transfected, as demonstrated by Western blot analysis in total cell extracts. No background levels of endoglin were observed in control cells transfected with the empty vector (Ø). By contrast, galectin-3 could be detected in all samples but, as expected, showed an increased signal in cells transfected with the galectin-3 expression vector. Co-immunoprecipitation studies of these cell lysates showed that galectin-3 was present in endoglin immunoprecipitates (Figure 1B). Conversely, endoglin was also detected in galectin-3 immunoprecipitates (Figure 1C).

Figure 1. Protein–protein association between galectin-3 and endoglin. (A–C). Co-immunoprecipitation of galectin-3 and endoglin. CHO-K1 cells were transiently transfected with pcEXV-Ø (Ø), pcEXV–HA–EngFL (Eng) and pcDNA3.1–Gal-3 (Gal3) expression vectors. (A) Total cell lysates (TCL) were analyzed by SDS-PAGE under reducing conditions, followed by Western blot (WB) analysis using specific antibodies to endoglin, galectin-3 and β-actin (loading control). Cell lysates were subjected to immunoprecipitation (IP) with anti-endoglin (B) or anti-galectin-3 (C) antibodies, followed by SDS-PAGE under reducing conditions and WB analysis with anti-endoglin or anti-galectin-3 antibodies, as indicated. Negative controls with an IgG2b (B) and IgG1 (C) were included. (D) Protein-protein interactions between galectin-3 and endoglin using Bio-layer interferometry (BLItz). The Ni–NTA biosensors tips were loaded with 7.3 µM recombinant human galectin-3/6xHis at the C-terminus (LGALS3), and protein binding was measured against 0.1% BSA in PBS (negative control) or 4.1 µM soluble endoglin (sEng). Kinetic sensorgrams were obtained using a single channel ForteBioBLItzTM instrument.

Figure 2.Galectin-3 and endoglin co-localize in human endothelial cells. Human umbilical vein-derived endothelial cell (HUVEC) monolayers were fixed with paraformaldehyde, permeabilized with Triton X-100, incubated with the mouse mAb P4A4 anti-endoglin, washed, and incubated with a rabbit polyclonal anti-galectin-3 antibody (PA5-34819). Galectin-3 and endoglin were detected by immunofluorescence upon incubation with Alexa 647 goat anti-rabbit IgG (red staining) and Alexa 488 goat anti-mouse IgG (green staining) secondary antibodies, respectively. (A) Single staining of galectin-3 (red) and endoglin (green) at the indicated magnifications. (B) Merge images plus DAPI (nuclear staining in blue) show co-localization of galectin-3 and endoglin (yellow color). Representative images of five different experiments are shown.

Endoglin associates with the cullin-type E3 ligase TRIM21

Figure 3.Protein–protein association between TRIM21 and endoglin. (A–E) Co-immunoprecipitation of TRIM21 and endoglin. A,B. HUVEC monolayers were lysed and total cell lysates (TCL) were subjected to SDS-PAGE under reducing (for TRIM21 detection) or nonreducing (for endoglin detection) conditions, followed by Western blot (WB) analysis using antibodies to endoglin, TRIM21 or β-actin (A). HUVECs lysates were subjected to immunoprecipitation (IP) with anti-TRIM21 or negative control antibodies, followed by WB analysis with anti-endoglin (B). C,D. CHO-K1 cells were transiently transfected with pDisplay–HA–Mock (Ø), pDisplay–HA–EngFL (E) or pcDNA3.1–HA–hTRIM21 (T) expression vectors, as indicated. Total cell lysates (TCL) were subjected to SDS-PAGE under nonreducing conditions and WB analysis using specific antibodies to endoglin, TRIM21, and β-actin (C). Cell lysates were subjected to immunoprecipitation (IP) with anti-TRIM21 or anti-endoglin antibodies, followed by SDS-PAGE under reducing (upper panel) or nonreducing (lower panel) conditions and WB analysis with anti-TRIM21 or anti-endoglin antibodies. Negative controls of appropriate IgG were included (D). E. CHO-K1 cells were transiently transfected with pcDNA3.1–HA–hTRIM21 and pDisplay–HA–Mock (Ø), pDisplay–HA–EngFL (FL; full-length), pDisplay–HA–EngEC (EC; cytoplasmic-less) or pDisplay–HA–EngTMEC (TMEC; cytoplasmic-less) expression vectors, as indicated. Cell lysates were subjected to immunoprecipitation with anti-TRIM21, followed by SDS-PAGE under reducing conditions and WB analysis with anti-endoglin antibodies, as indicated. The asterisk indicates the presence of a nonspecific band. Mr, molecular reference; Eng, endoglin; TRIM, TRIM21. (F) Protein–protein interactions between TRIM21 and endoglin using Bio-layer interferometry (BLItz). The Ni–NTA biosensors tips were loaded with 5.4 µM recombinant human TRIM21/6xHis at the N-terminus (R052), and protein binding was measured against 0.1% BSA in PBS (negative control) or 4.1 µM soluble endoglin (sEng). Kinetic sensorgrams were obtained using a single channel ForteBioBLItzTM instrument.

Table 1. Human protein-array analysis of endoglin interactors¹.

Accession #	Protein Name	Cellular Compartment
NM_172160.1	Potassium voltage-gated channel, shaker-related subfamily, beta member 1 (KCNAB1), transcript variant 1	Plasma membrane
Q14722
NM_138565.1	Cortactin (CTTN), transcript variant 2	Plasma membrane
Q14247
BC036123.1	Stromal membrane-associated protein 1 (SMAP1)	Plasma membrane
Q8IYB5
NM_173822.1	Family with sequence similarity 126, member B (FAM126B)	Plasma membrane, cytosol
Q8IXS8
BC047536.1	Sciellin (SCEL)	Plasma membrane, extracellular or secreted
O95171
BC068068.1	Galectin-3	Plasma membrane, mitochondrion, nucleus, extracellular or secreted
P17931
BC001247.1	Actin-binding LIM protein 1 (ABLIM1)	Cytoskeleton
O14639
NM_198943.1	Family with sequence similarity 39, member B (FAM39B)	Endosome, cytoskeleton
Q6VEQ5
NM_005898.4	Cell cycle associated protein 1 (CAPRIN1), transcript variant 1	Cytosol
Q14444
BC002559.1	YTH domain family, member 2 (YTHDF2)	Nucleus, cytosol
Q9Y5A9
NM_003141.2	Tripartite motif-containing 21 (TRIM21)	Nucleus, cytosol
P19474
BC025279.1	Scaffold attachment factor B2 (SAFB2)	Nucleus
Q14151
BC031650.1	Putative E3 ubiquitin-protein ligase SH3RF2	Nucleus
Q8TEC5
BC034488.2	ATP-binding cassette, sub-family F (GCN20), member 1 (ABCF1)	Nucleus
Q8NE71
BC040946.1	Spliceosome-associated protein CWC15 homolog (HSPC148)	Nucleus
Q9P013
NM_003609.2	HIRA interacting protein 3 (HIRIP3)	Nucleus
Q9BW71
NM_005572.1	Lamin A/C (LMNA), transcript variant 2	Nucleus
P02545
NM_006479.2	RAD51 associated protein 1 (RAD51AP1)	Nucleus
Q96B01
NM_014321.2	Origin recognition complex, subunit 6 like (yeast) (ORC6L)	Nucleus
Q9Y5N6
NM_015138.2	RNA polymerase-associated protein RTF1 homolog (RTF1)	Nucleus
Q92541
NM_032141.1	Coiled-coil domain containing 55 (CCDC55), transcript variant 1	Nucleus
Q9H0G5
BC012289.1	Protein PRRC2B, KIAA0515	Data not available
Q5JSZ5

¹ Microarrays containing over 9000 unique human proteins were screened using recombinant sEng as a probe. Protein interactors showing the highest scores (Z-score ≥2.0) are listed. GeneBank (https://www.ncbi.nlm.nih.gov/genbank/) and UniProtKB (https://www.uniprot.org/help/uniprotkb) accession numbers are indicated with a yellow or green background, respectively. The cellular compartment of each protein was obtained from the UniProtKB webpage. Proteins selected for further studies (TRIM21 and galectin-3) are indicated in bold type with blue background.

Note: the following are from NCBI Genbank and Genecards on TRIM21

 From Genbank: https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=DetailsSearch&Term=6737

TRIM21 tripartite motif containing 21 [ Homo sapiens (human) ]

Gene ID: 6737, updated on 6-Sep-2022

Summary

Official Symbol TRIM21provided by HGNC Official Full Name tripartite motif containing 21provided by HGNC Primary source HGNC:HGNC:11312 See related Ensembl:ENSG00000132109MIM:109092;AllianceGenome:HGNC:11312 Gene type protein coding RefSeq status REVIEWED Organism Homo sapiens Lineage Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo Also known as SSA; RO52; SSA1; RNF81; Ro/SSA Summary This gene encodes a member of the tripartite motif (TRIM) family. The TRIM motif includes three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil region. The encoded protein is part of the RoSSA ribonucleoprotein, which includes a single polypeptide and one of four small RNA molecules. The RoSSA particle localizes to both the cytoplasm and the nucleus. RoSSA interacts with autoantigens in patients with Sjogren syndrome and systemic lupus erythematosus. Alternatively spliced transcript variants for this gene have been described but the full-length nature of only one has been determined. [provided by RefSeq, Jul 2008] Expression Ubiquitous expression in spleen (RPKM 15.5), appendix (RPKM 13.2) and 24 other tissues See more Orthologs mouseall NEW Try the new Gene table
Try the new Transcript table

Genomic context

See TRIM21 in Genome Data Viewer Location:   11p15.4 Exon count:   7

Annotation release	Status	Assembly	Chr	Location
110	current	GRCh38.p14 (GCF_000001405.40)	11	NC_000011.10 (4384897..4393702, complement)
110	current	T2T-CHM13v2.0 (GCF_009914755.1)	11	NC_060935.1 (4449988..4458819, complement)
105.20220307	previous assembly	GRCh37.p13 (GCF_000001405.25)	11	NC_000011.9 (4406127..4414932, complement)

Chromosome 11 – NC_000011.10

Bibliography

Related articles in PubMed

1. TRIM21 inhibits the osteogenic differentiation of mesenchymal stem cells by facilitating K48 ubiquitination-mediated degradation of Akt.Xian J, et al. Exp Cell Res, 2022 Mar 15. PMID 35051432
2. A Promising Intracellular Protein-Degradation Strategy: TRIMbody-Away Technique Based on Nanobody Fragment.Chen G, et al. Biomolecules, 2021 Oct 14. PMID 34680146, Free PMC Article
3. Induced TRIM21 ISGylation by IFN-β enhances p62 ubiquitination to prevent its autophagosome targeting.Jin J, et al. Cell Death Dis, 2021 Jul 13. PMID 34257278, Free PMC Article
4. TRIM21 Polymorphisms are associated with Susceptibility and Clinical Status of Oral Squamous Cell Carcinoma patients.Chuang CY, et al. Int J Med Sci, 2021. PMID 34220328, Free PMC Article
5. TRIM21 inhibits porcine epidemic diarrhea virus proliferation by proteasomal degradation of the nucleocapsid protein.Wang H, et al. Arch Virol, 2021 Jul. PMID 33900472, Free PMC Article

From GeneCard:https://www.genecards.org/cgi-bin/carddisp.pl?gene=TRIM21

Entrez Gene Summary for TRIM21 Gene

• This gene encodes a member of the tripartite motif (TRIM) family. The TRIM motif includes three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil region. The encoded protein is part of the RoSSA ribonucleoprotein, which includes a single polypeptide and one of four small RNA molecules. The RoSSA particle localizes to both the cytoplasm and the nucleus. RoSSA interacts with autoantigens in patients with Sjogren syndrome and systemic lupus erythematosus. Alternatively spliced transcript variants for this gene have been described but the full-length nature of only one has been determined. [provided by RefSeq, Jul 2008]

GeneCards Summary for TRIM21 Gene

TRIM21 (Tripartite Motif Containing 21) is a Protein Coding gene. Diseases associated with TRIM21 include Heart Block, Congenital and Sjogren Syndrome. Among its related pathways are Cytosolic sensors of pathogen-associated DNA and KEAP1-NFE2L2 pathway. Gene Ontology (GO) annotations related to this gene include identical protein binding and ligase activity. An important paralog of this gene is TRIM6.

UniProtKB/Swiss-Prot Summary for TRIM21 Gene

E3 ubiquitin-protein ligase whose activity is dependent on E2 enzymes, UBE2D1, UBE2D2, UBE2E1 and UBE2E2. Forms a ubiquitin ligase complex in cooperation with the E2 UBE2D2 that is used not only for the ubiquitination of USP4 and IKBKB but also for its self-ubiquitination. Component of cullin-RING-based SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complexes such as SCF(SKP2)-like complexes. A TRIM21-containing SCF(SKP2)-like complex is shown to mediate ubiquitination of CDKN1B (‘Thr-187’ phosphorylated-form), thereby promoting its degradation by the proteasome. Monoubiquitinates IKBKB that will negatively regulates Tax-induced NF-kappa-B signaling. Negatively regulates IFN-beta production post-pathogen recognition by polyubiquitin-mediated degradation of IRF3. Mediates the ubiquitin-mediated proteasomal degradation of IgG1 heavy chain, which is linked to the VCP-mediated ER-associated degradation (ERAD) pathway. Promotes IRF8 ubiquitination, which enhanced the ability of IRF8 to stimulate cytokine genes transcription in macrophages. Plays a role in the regulation of the cell cycle progression. Enhances the decapping activity of DCP2. Exists as a ribonucleoprotein particle present in all mammalian cells studied and composed of a single polypeptide and one of four small RNA molecules. At least two isoforms are present in nucleated and red blood cells, and tissue specific differences in RO/SSA proteins have been identified. The common feature of these proteins is their ability to bind HY RNAs.2. Involved in the regulation of innate immunity and the inflammatory response in response to IFNG/IFN-gamma. Organizes autophagic machinery by serving as a platform for the assembly of ULK1, Beclin 1/BECN1 and ATG8 family members and recognizes specific autophagy targets, thus coordinating target recognition with assembly of the autophagic apparatus and initiation of autophagy. Acts as an autophagy receptor for the degradation of IRF3, hence attenuating type I interferon (IFN)-dependent immune responses (PubMed:26347139, 16297862, 16316627, 16472766, 16880511, 18022694, 18361920, 18641315, 18845142, 19675099). Represses the innate antiviral response by facilitating the formation of the NMI-IFI35 complex through ‘Lys-63’-linked ubiquitination of NMI (PubMed:26342464). ( RO52_HUMAN,P19474 )

Molecular function for TRIM21 Gene according to UniProtKB/Swiss-Prot

Function:

• E3 ubiquitin-protein ligase whose activity is dependent on E2 enzymes, UBE2D1, UBE2D2, UBE2E1 and UBE2E2.
  Forms a ubiquitin ligase complex in cooperation with the E2 UBE2D2 that is used not only for the ubiquitination of USP4 and IKBKB but also for its self-ubiquitination.
  Component of cullin-RING-based SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complexes such as SCF(SKP2)-like complexes.
  A TRIM21-containing SCF(SKP2)-like complex is shown to mediate ubiquitination of CDKN1B (‘Thr-187’ phosphorylated-form), thereby promoting its degradation by the proteasome.
  Monoubiquitinates IKBKB that will negatively regulates Tax-induced NF-kappa-B signaling.
  Negatively regulates IFN-beta production post-pathogen recognition by polyubiquitin-mediated degradation of IRF3.
  Mediates the ubiquitin-mediated proteasomal degradation of IgG1 heavy chain, which is linked to the VCP-mediated ER-associated degradation (ERAD) pathway.
  Promotes IRF8 ubiquitination, which enhanced the ability of IRF8 to stimulate cytokine genes transcription in macrophages.
  Plays a role in the regulation of the cell cycle progression.

Endoglin Protein Interactome Profiling Identifies TRIM21 and Galectin-3 as New Binding Partners

Gallardo-Vara E, Ruiz-Llorente L, Casado-Vela J, Ruiz-Rodríguez MJ, López-Andrés N, Pattnaik AK, Quintanilla M, Bernabeu C. Endoglin Protein Interactome Profiling Identifies TRIM21 and Galectin-3 as New Binding Partners. Cells. 2019 Sep 13;8(9):1082. doi: 10.3390/cells8091082. PMID: 31540324; PMCID: PMC6769930.

Abstract

Endoglin is a 180-kDa glycoprotein receptor primarily expressed by the vascular endothelium and involved in cardiovascular disease and cancer. Heterozygous mutations in the endoglin gene (ENG) cause hereditary hemorrhagic telangiectasia type 1, a vascular disease that presents with nasal and gastrointestinal bleeding, skin and mucosa telangiectases, and arteriovenous malformations in internal organs. A circulating form of endoglin (alias soluble endoglin, sEng), proteolytically released from the membrane-bound protein, has been observed in several inflammation-related pathological conditions and appears to contribute to endothelial dysfunction and cancer development through unknown mechanisms. Membrane-bound endoglin is an auxiliary component of the TGF-β receptor complex and the extracellular region of endoglin has been shown to interact with types I and II TGF-β receptors, as well as with BMP9 and BMP10 ligands, both members of the TGF-β family. To search for novel protein interactors, we screened a microarray containing over 9000 unique human proteins using recombinant sEng as bait. We find that sEng binds with high affinity, at least, to 22 new proteins. Among these, we validated the interaction of endoglin with galectin-3, a secreted member of the lectin family with capacity to bind membrane glycoproteins, and with tripartite motif-containing protein 21 (TRIM21), an E3 ubiquitin-protein ligase. Using human endothelial cells and Chinese hamster ovary cells, we showed that endoglin co-immunoprecipitates and co-localizes with galectin-3 or TRIM21. These results open new research avenues on endoglin function and regulation.

 

Source: https://www.mdpi.com/2073-4409/8/9/1082/htm

 

Endoglin is an auxiliary TGF-β co-receptor predominantly expressed in endothelial cells, which is involved in vascular development, repair, homeostasis, and disease [1,2,3,4]. Heterozygous mutations in the human ENDOGLIN gene (ENG) cause hereditary hemorrhagic telangiectasia (HHT) type 1, a vascular disease associated with nasal and gastrointestinal bleeds, telangiectases on skin and mucosa and arteriovenous malformations in the lung, liver, and brain [4,5,6]. The key role of endoglin in the vasculature is also illustrated by the fact that endoglin-KO mice die in utero due to defects in the vascular system [7]. Endoglin expression is markedly upregulated in proliferating endothelial cells involved in active angiogenesis, including the solid tumor neovasculature [8,9]. For this reason, endoglin has become a promising target for the antiangiogenic treatment of cancer [10,11,12]. Endoglin is also expressed in cancer cells where it can behave as both a tumor suppressor in prostate, breast, esophageal, and skin carcinomas [13,14,15,16] and a promoter of malignancy in melanoma and Ewing’s sarcoma [17]. Ectodomain shedding of membrane-bound endoglin may lead to a circulating form of the protein, also known as soluble endoglin (sEng) [18,19,20]. Increased levels of sEng have been found in several vascular-related pathologies, including preeclampsia, a disease of high prevalence in pregnant women which, if left untreated, can lead to serious and even fatal complications for both mother and baby [2,18,19,21]. Interestingly, several lines of evidence support a pathogenic role of sEng in the vascular system, including endothelial dysfunction, antiangiogenic activity, increased vascular permeability, inflammation-associated leukocyte adhesion and transmigration, and hypertension [18,22,23,24,25,26,27]. Because of its key role in vascular pathology, a large number of studies have addressed the structure and function of endoglin at the molecular level, in order to better understand its mechanism of action.

 

 Galectin-3 Interacts with Endoglin in Cells

Galectin-3 is a secreted member of the lectin family with the capacity to bind membrane glycoproteins like endoglin and is involved in the pathogenesis of many human diseases [52]. We confirmed the protein screen data for galectin-3, as evidenced by two-way co-immunoprecipitation of endoglin and galectin-3 upon co-transfection in CHO-K1 cells. As shown in Figure 1A, galectin-3 and endoglin were efficiently transfected, as demonstrated by Western blot analysis in total cell extracts. No background levels of endoglin were observed in control cells transfected with the empty vector (Ø). By contrast, galectin-3 could be detected in all samples but, as expected, showed an increased signal in cells transfected with the galectin-3 expression vector. Co-immunoprecipitation studies of these cell lysates showed that galectin-3 was present in endoglin immunoprecipitates (Figure 1B). Conversely, endoglin was also detected in galectin-3 immunoprecipitates (Figure 1C).

Figure 1. Protein–protein association between galectin-3 and endoglin. (A–C). Co-immunoprecipitation of galectin-3 and endoglin. CHO-K1 cells were transiently transfected with pcEXV-Ø (Ø), pcEXV–HA–EngFL (Eng) and pcDNA3.1–Gal-3 (Gal3) expression vectors. (A) Total cell lysates (TCL) were analyzed by SDS-PAGE under reducing conditions, followed by Western blot (WB) analysis using specific antibodies to endoglin, galectin-3 and β-actin (loading control). Cell lysates were subjected to immunoprecipitation (IP) with anti-endoglin (B) or anti-galectin-3 (C) antibodies, followed by SDS-PAGE under reducing conditions and WB analysis with anti-endoglin or anti-galectin-3 antibodies, as indicated. Negative controls with an IgG2b (B) and IgG1 (C) were included. (D) Protein-protein interactions between galectin-3 and endoglin using Bio-layer interferometry (BLItz). The Ni–NTA biosensors tips were loaded with 7.3 µM recombinant human galectin-3/6xHis at the C-terminus (LGALS3), and protein binding was measured against 0.1% BSA in PBS (negative control) or 4.1 µM soluble endoglin (sEng). Kinetic sensorgrams were obtained using a single channel ForteBioBLItzTM instrument.

Figure 2. Galectin-3 and endoglin co-localize in human endothelial cells. Human umbilical vein-derived endothelial cell (HUVEC) monolayers were fixed with paraformaldehyde, permeabilized with Triton X-100, incubated with the mouse mAb P4A4 anti-endoglin, washed, and incubated with a rabbit polyclonal anti-galectin-3 antibody (PA5-34819). Galectin-3 and endoglin were detected by immunofluorescence upon incubation with Alexa 647 goat anti-rabbit IgG (red staining) and Alexa 488 goat anti-mouse IgG (green staining) secondary antibodies, respectively. (A) Single staining of galectin-3 (red) and endoglin (green) at the indicated magnifications. (B) Merge images plus DAPI (nuclear staining in blue) show co-localization of galectin-3 and endoglin (yellow color). Representative images of five different experiments are shown.

  

Endoglin associates with the cullin-type E3 ligase TRIM21

 

Figure 3. Protein–protein association between TRIM21 and endoglin. (A–E) Co-immunoprecipitation of TRIM21 and endoglin. A,B. HUVEC monolayers were lysed and total cell lysates (TCL) were subjected to SDS-PAGE under reducing (for TRIM21 detection) or nonreducing (for endoglin detection) conditions, followed by Western blot (WB) analysis using antibodies to endoglin, TRIM21 or β-actin (A). HUVECs lysates were subjected to immunoprecipitation (IP) with anti-TRIM21 or negative control antibodies, followed by WB analysis with anti-endoglin (B). C,D. CHO-K1 cells were transiently transfected with pDisplay–HA–Mock (Ø), pDisplay–HA–EngFL (E) or pcDNA3.1–HA–hTRIM21 (T) expression vectors, as indicated. Total cell lysates (TCL) were subjected to SDS-PAGE under nonreducing conditions and WB analysis using specific antibodies to endoglin, TRIM21, and β-actin (C). Cell lysates were subjected to immunoprecipitation (IP) with anti-TRIM21 or anti-endoglin antibodies, followed by SDS-PAGE under reducing (upper panel) or nonreducing (lower panel) conditions and WB analysis with anti-TRIM21 or anti-endoglin antibodies. Negative controls of appropriate IgG were included (D). E. CHO-K1 cells were transiently transfected with pcDNA3.1–HA–hTRIM21 and pDisplay–HA–Mock (Ø), pDisplay–HA–EngFL (FL; full-length), pDisplay–HA–EngEC (EC; cytoplasmic-less) or pDisplay–HA–EngTMEC (TMEC; cytoplasmic-less) expression vectors, as indicated. Cell lysates were subjected to immunoprecipitation with anti-TRIM21, followed by SDS-PAGE under reducing conditions and WB analysis with anti-endoglin antibodies, as indicated. The asterisk indicates the presence of a nonspecific band. Mr, molecular reference; Eng, endoglin; TRIM, TRIM21. (F) Protein–protein interactions between TRIM21 and endoglin using Bio-layer interferometry (BLItz). The Ni–NTA biosensors tips were loaded with 5.4 µM recombinant human TRIM21/6xHis at the N-terminus (R052), and protein binding was measured against 0.1% BSA in PBS (negative control) or 4.1 µM soluble endoglin (sEng). Kinetic sensorgrams were obtained using a single channel ForteBioBLItzTM instrument.

 

Table 1. Human protein-array analysis of endoglin interactors¹.

Accession #	Protein Name	Cellular Compartment
NM_172160.1	Potassium voltage-gated channel, shaker-related subfamily, beta member 1 (KCNAB1), transcript variant 1	Plasma membrane
Q14722
NM_138565.1	Cortactin (CTTN), transcript variant 2	Plasma membrane
Q14247
BC036123.1	Stromal membrane-associated protein 1 (SMAP1)	Plasma membrane
Q8IYB5
NM_173822.1	Family with sequence similarity 126, member B (FAM126B)	Plasma membrane, cytosol
Q8IXS8
BC047536.1	Sciellin (SCEL)	Plasma membrane, extracellular or secreted
O95171
BC068068.1	Galectin-3	Plasma membrane, mitochondrion, nucleus, extracellular or secreted
P17931
BC001247.1	Actin-binding LIM protein 1 (ABLIM1)	Cytoskeleton
O14639
NM_198943.1	Family with sequence similarity 39, member B (FAM39B)	Endosome, cytoskeleton
Q6VEQ5
NM_005898.4	Cell cycle associated protein 1 (CAPRIN1), transcript variant 1	Cytosol
Q14444
BC002559.1	YTH domain family, member 2 (YTHDF2)	Nucleus, cytosol
Q9Y5A9
NM_003141.2	Tripartite motif-containing 21 (TRIM21)	Nucleus, cytosol
P19474
BC025279.1	Scaffold attachment factor B2 (SAFB2)	Nucleus
Q14151
BC031650.1	Putative E3 ubiquitin-protein ligase SH3RF2	Nucleus
Q8TEC5
BC034488.2	ATP-binding cassette, sub-family F (GCN20), member 1 (ABCF1)	Nucleus
Q8NE71
BC040946.1	Spliceosome-associated protein CWC15 homolog (HSPC148)	Nucleus
Q9P013
NM_003609.2	HIRA interacting protein 3 (HIRIP3)	Nucleus
Q9BW71
NM_005572.1	Lamin A/C (LMNA), transcript variant 2	Nucleus
P02545
NM_006479.2	RAD51 associated protein 1 (RAD51AP1)	Nucleus
Q96B01
NM_014321.2	Origin recognition complex, subunit 6 like (yeast) (ORC6L)	Nucleus
Q9Y5N6
NM_015138.2	RNA polymerase-associated protein RTF1 homolog (RTF1)	Nucleus
Q92541
NM_032141.1	Coiled-coil domain containing 55 (CCDC55), transcript variant 1	Nucleus
Q9H0G5
BC012289.1	Protein PRRC2B, KIAA0515	Data not available
Q5JSZ5

¹ Microarrays containing over 9000 unique human proteins were screened using recombinant sEng as a probe. Protein interactors showing the highest scores (Z-score ≥2.0) are listed. GeneBank (https://www.ncbi.nlm.nih.gov/genbank/) and UniProtKB (https://www.uniprot.org/help/uniprotkb) accession numbers are indicated with a yellow or green background, respectively. The cellular compartment of each protein was obtained from the UniProtKB webpage. Proteins selected for further studies (TRIM21 and galectin-3) are indicated in bold type with blue background.

  

Note: the following are from NCBI Genbank and Genecards on TRIM21

 From Genbank: https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=DetailsSearch&Term=6737

TRIM21 tripartite motif containing 21 [ Homo sapiens (human) ]

Gene ID: 6737, updated on 6-Sep-2022

Summary

Official Symbol

TRIM21provided by HGNC

Official Full Name

tripartite motif containing 21provided by HGNC

Primary source

HGNC:HGNC:11312

See related

Ensembl:ENSG00000132109 MIM:109092; AllianceGenome:HGNC:11312

Gene type

protein coding

RefSeq status

REVIEWED

Organism

Homo sapiens

Lineage

Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo

Also known as

SSA; RO52; SSA1; RNF81; Ro/SSA

Summary

This gene encodes a member of the tripartite motif (TRIM) family. The TRIM motif includes three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil region. The encoded protein is part of the RoSSA ribonucleoprotein, which includes a single polypeptide and one of four small RNA molecules. The RoSSA particle localizes to both the cytoplasm and the nucleus. RoSSA interacts with autoantigens in patients with Sjogren syndrome and systemic lupus erythematosus. Alternatively spliced transcript variants for this gene have been described but the full-length nature of only one has been determined. [provided by RefSeq, Jul 2008]

Expression

Ubiquitous expression in spleen (RPKM 15.5), appendix (RPKM 13.2) and 24 other tissues See more

Orthologs

mouse all

NEW

Try the new Gene table
Try the new Transcript table

Genomic context

 

See TRIM21 in Genome Data Viewer

Location:

11p15.4

Exon count:

7

Annotation release	Status	Assembly	Chr	Location
110	current	GRCh38.p14 (GCF_000001405.40)	11	NC_000011.10 (4384897..4393702, complement)
110	current	T2T-CHM13v2.0 (GCF_009914755.1)	11	NC_060935.1 (4449988..4458819, complement)
105.20220307	previous assembly	GRCh37.p13 (GCF_000001405.25)	11	NC_000011.9 (4406127..4414932, complement)

Chromosome 11 – NC_000011.10

 

 

Bibliography

 

Related articles in PubMed

1. TRIM21 inhibits the osteogenic differentiation of mesenchymal stem cells by facilitating K48 ubiquitination-mediated degradation of Akt.Xian J, et al. Exp Cell Res, 2022 Mar 15. PMID 35051432
2. A Promising Intracellular Protein-Degradation Strategy: TRIMbody-Away Technique Based on Nanobody Fragment.Chen G, et al. Biomolecules, 2021 Oct 14. PMID 34680146, Free PMC Article
3. Induced TRIM21 ISGylation by IFN-β enhances p62 ubiquitination to prevent its autophagosome targeting.Jin J, et al. Cell Death Dis, 2021 Jul 13. PMID 34257278, Free PMC Article
4. TRIM21 Polymorphisms are associated with Susceptibility and Clinical Status of Oral Squamous Cell Carcinoma patients.Chuang CY, et al. Int J Med Sci, 2021. PMID 34220328, Free PMC Article
5. TRIM21 inhibits porcine epidemic diarrhea virus proliferation by proteasomal degradation of the nucleocapsid protein.Wang H, et al. Arch Virol, 2021 Jul. PMID 33900472, Free PMC Article

From GeneCard: https://www.genecards.org/cgi-bin/carddisp.pl?gene=TRIM21

 

Entrez Gene Summary for TRIM21 Gene

• This gene encodes a member of the tripartite motif (TRIM) family. The TRIM motif includes three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil region. The encoded protein is part of the RoSSA ribonucleoprotein, which includes a single polypeptide and one of four small RNA molecules. The RoSSA particle localizes to both the cytoplasm and the nucleus. RoSSA interacts with autoantigens in patients with Sjogren syndrome and systemic lupus erythematosus. Alternatively spliced transcript variants for this gene have been described but the full-length nature of only one has been determined. [provided by RefSeq, Jul 2008]

GeneCards Summary for TRIM21 Gene

TRIM21 (Tripartite Motif Containing 21) is a Protein Coding gene. Diseases associated with TRIM21 include Heart Block, Congenital and Sjogren Syndrome. Among its related pathways are Cytosolic sensors of pathogen-associated DNA and KEAP1-NFE2L2 pathway. Gene Ontology (GO) annotations related to this gene include identical protein binding and ligase activity. An important paralog of this gene is TRIM6.

UniProtKB/Swiss-Prot Summary for TRIM21 Gene

E3 ubiquitin-protein ligase whose activity is dependent on E2 enzymes, UBE2D1, UBE2D2, UBE2E1 and UBE2E2. Forms a ubiquitin ligase complex in cooperation with the E2 UBE2D2 that is used not only for the ubiquitination of USP4 and IKBKB but also for its self-ubiquitination. Component of cullin-RING-based SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complexes such as SCF(SKP2)-like complexes. A TRIM21-containing SCF(SKP2)-like complex is shown to mediate ubiquitination of CDKN1B (‘Thr-187’ phosphorylated-form), thereby promoting its degradation by the proteasome. Monoubiquitinates IKBKB that will negatively regulates Tax-induced NF-kappa-B signaling. Negatively regulates IFN-beta production post-pathogen recognition by polyubiquitin-mediated degradation of IRF3. Mediates the ubiquitin-mediated proteasomal degradation of IgG1 heavy chain, which is linked to the VCP-mediated ER-associated degradation (ERAD) pathway. Promotes IRF8 ubiquitination, which enhanced the ability of IRF8 to stimulate cytokine genes transcription in macrophages. Plays a role in the regulation of the cell cycle progression. Enhances the decapping activity of DCP2. Exists as a ribonucleoprotein particle present in all mammalian cells studied and composed of a single polypeptide and one of four small RNA molecules. At least two isoforms are present in nucleated and red blood cells, and tissue specific differences in RO/SSA proteins have been identified. The common feature of these proteins is their ability to bind HY RNAs.2. Involved in the regulation of innate immunity and the inflammatory response in response to IFNG/IFN-gamma. Organizes autophagic machinery by serving as a platform for the assembly of ULK1, Beclin 1/BECN1 and ATG8 family members and recognizes specific autophagy targets, thus coordinating target recognition with assembly of the autophagic apparatus and initiation of autophagy. Acts as an autophagy receptor for the degradation of IRF3, hence attenuating type I interferon (IFN)-dependent immune responses (PubMed:26347139, 16297862, 16316627, 16472766, 16880511, 18022694, 18361920, 18641315, 18845142, 19675099). Represses the innate antiviral response by facilitating the formation of the NMI-IFI35 complex through ‘Lys-63’-linked ubiquitination of NMI (PubMed:26342464). ( RO52_HUMAN,P19474 )

Molecular function for TRIM21 Gene according to UniProtKB/Swiss-Prot

Function:

• E3 ubiquitin-protein ligase whose activity is dependent on E2 enzymes, UBE2D1, UBE2D2, UBE2E1 and UBE2E2.
  Forms a ubiquitin ligase complex in cooperation with the E2 UBE2D2 that is used not only for the ubiquitination of USP4 and IKBKB but also for its self-ubiquitination.
  Component of cullin-RING-based SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complexes such as SCF(SKP2)-like complexes.
  A TRIM21-containing SCF(SKP2)-like complex is shown to mediate ubiquitination of CDKN1B (‘Thr-187’ phosphorylated-form), thereby promoting its degradation by the proteasome.
  Monoubiquitinates IKBKB that will negatively regulates Tax-induced NF-kappa-B signaling.
  Negatively regulates IFN-beta production post-pathogen recognition by polyubiquitin-mediated degradation of IRF3.
  Mediates the ubiquitin-mediated proteasomal degradation of IgG1 heavy chain, which is linked to the VCP-mediated ER-associated degradation (ERAD) pathway.
  Promotes IRF8 ubiquitination, which enhanced the ability of IRF8 to stimulate cytokine genes transcription in macrophages.
  Plays a role in the regulation of the cell cycle progression.

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The Human Genome Gets Fully Sequenced: A Simplistic Take on Century Long Effort

Posted in Big Data, Bio Instrumentation in Experimental Life Sciences Research, BioIT: BioInformatics, BioIT: BioInformatics, NGS, Clinical & Translational, Pharmaceutical R&D Informatics, Clinical Genomics, Cancer Informatics, Biological Networks, Gene Regulation and Evolution, Disease Biology, Genome Biology, Next Generation Sequencing (NGS), Nobel Prize Winners, Single-cell sequencing, Variation in human protein-coding regions, tagged AAAS, Craig Venter, DNA Sequencing, genetic variants, Human Genome Project, Jennifer Doudna, junk DNA, telomere consortium on June 14, 2022| Leave a Comment »

The Human Genome Gets Fully Sequenced: A Simplistic Take on Century Long Effort

 

Curator: Stephen J. Williams, PhD

Article ID #295: The Human Genome Gets Fully Sequenced: A Simplistic Take on Century Long Effort. Published on 6/14/2022

WordCloud Image Produced by Adam Tubman

Ever since the hard work by Rosalind Franklin to deduce structures of DNA and the coincidental work by Francis Crick and James Watson who modeled the basic building blocks of DNA, DNA has been considered as the basic unit of heredity and life, with the “Central Dogma” (DNA to RNA to Protein) at its core.  These were the discoveries in the early twentieth century, and helped drive the transformational shift of biological experimentation, from protein isolation and characterization to cloning protein-encoding genes to characterizing how the genes are expressed temporally, spatially, and contextually.

Rosalind Franklin, who’s crystolagraphic data led to determination of DNA structure. Shown as 1953 Time cover as Time person of the Year

Dr Francis Crick and James Watson in front of their model structure of DNA

 

 

 

 

 

 

 

 

 

Up to this point (1970s-mid 80s) , it was felt that genetic information was rather static, and the goal was still to understand and characterize protein structure and function while an understanding of the underlying genetic information was more important for efforts like linkage analysis of genetic defects and tools for the rapidly developing field of molecular biology.  But the development of the aforementioned molecular biology tools including DNA cloning, sequencing and synthesis, gave scientists the idea that a whole recording of the human genome might be possible and worth the effort.

How the Human Genome Project  Expanded our View of Genes Genetic Material and Biological Processes

 

 

From the Human Genome Project Information Archive

Source:  https://web.ornl.gov/sci/techresources/Human_Genome/project/hgp.shtml

History of the Human Genome Project

The Human Genome Project (HGP) refers to the international 13-year effort, formally begun in October 1990 and completed in 2003, to discover all the estimated 20,000-25,000 human genes and make them accessible for further biological study. Another project goal was to determine the complete sequence of the 3 billion DNA subunits (bases in the human genome). As part of the HGP, parallel studies were carried out on selected model organisms such as the bacterium E. coli and the mouse to help develop the technology and interpret human gene function. The DOE Human Genome Program and the NIH National Human Genome Research Institute (NHGRI) together sponsored the U.S. Human Genome Project.

 

Please see the following for goals, timelines, and funding for this project

 

History of the Project

• HGP Goals and Corresponding Completion Dates
• Budget History of the U.S. Human Genome Project
• Timeline: Major Events in the Human Genome Project

It is interesting to note that multiple government legislation is credited for the funding of such a massive project including

Project Enabling Legislation

• The Atomic Energy Act of 1946 (P.L. 79-585) provided the initial charter for a comprehensive program of research and development related to the utilization of fissionable and radioactive materials for medical, biological, and health purposes.
• The Atomic Energy Act of 1954 (P.L. 83-706) further authorized the AEC “to conduct research on the biologic effects of ionizing radiation.”
• The Energy Reorganization Act of 1974 (P.L. 93-438) provided that responsibilities of the Energy Research and Development Administration (ERDA) shall include “engaging in and supporting environmental, biomedical, physical, and safety research related to the development of energy resources and utilization technologies.”
• The Federal Non-nuclear Energy Research and Development Act of 1974 (P.L. 93-577) authorized ERDA to conduct a comprehensive non-nuclear energy research, development, and demonstration program to include the environmental and social consequences of the various technologies.
• The DOE Organization Act of 1977 (P.L. 95-91) mandated the Department “to assure incorporation of national environmental protection goals in the formulation and implementation of energy programs; and to advance the goal of restoring, protecting, and enhancing environmental quality, and assuring public health and safety,” and to conduct “a comprehensive program of research and development on the environmental effects of energy technology and program.”

It should also be emphasized that the project was not JUST funded through NIH but also Department of Energy

Project Sponsors

• The U.S. Department of Energy funded its Human Genome Program through their Office of Biological and Environmental Research. (genome@science.doe.gov).
• The U.S. National Institutes of Health funded its program through the National Human Genome Research Institute (NHGRI).

For a great read on Dr. Craig Ventnor with interviews with the scientist see Dr. Larry Bernstein’s excellent post The Human Genome Project

 

By 2003 we had gained much information about the structure of DNA, genes, exons, introns and allowed us to gain more insights into the diversity of genetic material and the underlying protein coding genes as well as many of the gene-expression regulatory elements.  However there was much uninvestigated material dispersed between genes, the then called “junk DNA” and, up to 2003 not much was known about the function of this ‘junk DNA’.  In addition there were two other problems:

• The reference DNA used was actually from one person (Craig Ventor who was the lead initiator of the project)
• Multiple gaps in the DNA sequence existed, and needed to be filled in

It is important to note that a tremendous amount of diversity of protein has been realized from both transcriptomic and proteomic studies.  Although about 20 to 25,000 coding genes exist the human proteome contains about 600,000 proteoforms (due to alternative splicing, posttranslational modifications etc.)

This expansion of the proteoform via alternate splicing into isoforms, gene duplication to paralogs has been shown to have major effects on, for example, cellular signaling pathways (1)

However just recently it has been reported that the FULL human genome has been sequenced and is complete and verified.  This was the focus of a recent issue in the journal Science.

Source: https://www.science.org/doi/10.1126/science.abj6987

Abstract

Since its initial release in 2000, the human reference genome has covered only the euchromatic fraction of the genome, leaving important heterochromatic regions unfinished. Addressing the remaining 8% of the genome, the Telomere-to-Telomere (T2T) Consortium presents a complete 3.055 billion–base pair sequence of a human genome, T2T-CHM13, that includes gapless assemblies for all chromosomes except Y, corrects errors in the prior references, and introduces nearly 200 million base pairs of sequence containing 1956 gene predictions, 99 of which are predicted to be protein coding. The completed regions include all centromeric satellite arrays, recent segmental duplications, and the short arms of all five acrocentric chromosomes, unlocking these complex regions of the genome to variational and functional studies.

 

The current human reference genome was released by the Genome Reference Consortium (GRC) in 2013 and most recently patched in 2019 (GRCh38.p13) (1). This reference traces its origin to the publicly funded Human Genome Project (2) and has been continually improved over the past two decades. Unlike the competing Celera effort (3) and most modern sequencing projects based on “shotgun” sequence assembly (4), the GRC assembly was constructed from sequenced bacterial artificial chromosomes (BACs) that were ordered and oriented along the human genome by means of radiation hybrid, genetic linkage, and fingerprint maps. However, limitations of BAC cloning led to an underrepresentation of repetitive sequences, and the opportunistic assembly of BACs derived from multiple individuals resulted in a mosaic of haplotypes. As a result, several GRC assembly gaps are unsolvable because of incompatible structural polymorphisms on their flanks, and many other repetitive and polymorphic regions were left unfinished or incorrectly assembled (5).

 

Fig. 1. Summary of the complete T2T-CHM13 human genome assembly.
(A) Ideogram of T2T-CHM13v1.1 assembly features. For each chromosome (chr), the following information is provided from bottom to top: gaps and issues in GRCh38 fixed by CHM13 overlaid with the density of genes exclusive to CHM13 in red; segmental duplications (SDs) (42) and centromeric satellites (CenSat) (30); and CHM13 ancestry predictions (EUR, European; SAS, South Asian; EAS, East Asian; AMR, ad-mixed American). Bottom scale is measured in Mbp. (B and C) Additional (nonsyntenic) bases in the CHM13 assembly relative to GRCh38 per chromosome, with the acrocentrics highlighted in black (B) and by sequence type (C). (Note that the CenSat and SD annotations overlap.) RepMask, RepeatMasker. (D) Total nongap bases in UCSC reference genome releases dating back to September 2000 (hg4) and ending with T2T-CHM13 in 2021. Mt/Y/Ns, mitochondria, chrY, and gaps.

Note in Figure 1D the exponential growth in genetic information.

Also very important is the ability to determine all the paralogs, isoforms, areas of potential epigenetic regulation, gene duplications, and transposable elements that exist within the human genome.

Analyses and resources

A number of companion studies were carried out to characterize the complete sequence of a human genome, including comprehensive analyses of centromeric satellites (30), segmental duplications (42), transcriptional (49) and epigenetic profiles (29), mobile elements (49), and variant calls (25). Up to 99% of the complete CHM13 genome can be confidently mapped with long-read sequencing, opening these regions of the genome to functional and variational analysis (23) (fig. S38 and table S14). We have produced a rich collection of annotations and omics datasets for CHM13—including RNA sequencing (RNA-seq) (30), Iso-seq (21), precision run-on sequencing (PRO-seq) (49), cleavage under targets and release using nuclease (CUT&RUN) (30), and ONT methylation (29) experiments—and have made these datasets available via a centralized University of California, Santa Cruz (UCSC), Assembly Hub genome browser (54).

 

To highlight the utility of these genetic and epigenetic resources mapped to a complete human genome, we provide the example of a segmentally duplicated region of the chromosome 4q subtelomere that is associated with facioscapulohumeral muscular dystrophy (FSHD) (55). This region includes FSHD region gene 1 (FRG1), FSHD region gene 2 (FRG2), and an intervening D4Z4 macrosatellite repeat containing the double homeobox 4 (DUX4) gene that has been implicated in the etiology of FSHD (56). Numerous duplications of this region throughout the genome have complicated past genetic analyses of FSHD.

The T2T-CHM13 assembly reveals 23 paralogs of FRG1 spread across all acrocentric chromosomes as well as chromosomes 9 and 20 (Fig. 5A). This gene appears to have undergone recent amplification in the great apes (57), and approximate locations of FRG1 paralogs were previously identified by FISH (58). However, only nine FRG1 paralogs are found in GRCh38, hampering sequence-based analysis.

Future of the human reference genome

The T2T-CHM13 assembly adds five full chromosome arms and more additional sequence than any genome reference release in the past 20 years (Fig. 1D). This 8% of the genome has not been overlooked because of a lack of importance but rather because of technological limitations. High-accuracy long-read sequencing has finally removed this technological barrier, enabling comprehensive studies of genomic variation across the entire human genome, which we expect to drive future discovery in human genomic health and disease. Such studies will necessarily require a complete and accurate human reference genome.

CHM13 lacks a Y chromosome, and homozygous Y-bearing CHMs are nonviable, so a different sample type will be required to complete this last remaining chromosome. However, given its haploid nature, it should be possible to assemble the Y chromosome from a male sample using the same methods described here and supplement the T2T-CHM13 reference assembly with a Y chromosome as needed.

Extending beyond the human reference genome, large-scale resequencing projects have revealed genomic variation across human populations. Our reanalyses of the 1KGP (25) and SGDP (42) datasets have already shown the advantages of T2T-CHM13, even for short-read analyses. However, these studies give only a glimpse of the extensive structural variation that lies within the most repetitive regions of the genome assembled here. Long-read resequencing studies are now needed to comprehensively survey polymorphic variation and reveal any phenotypic associations within these regions.

Although CHM13 represents a complete human haplotype, it does not capture the full diversity of human genetic variation. To address this bias, the Human Pangenome Reference Consortium (59) has joined with the T2T Consortium to build a collection of high-quality reference haplotypes from a diverse set of samples. Ideally, all genomes could be assembled at the quality achieved here, but automated T2T assembly of diploid genomes presents a difficult challenge that will require continued development. Until this goal is realized, and any human genome can be completely sequenced without error, the T2T-CHM13 assembly represents a more complete, representative, and accurate reference than GRCh38.

 

This paper was the focus of a Time article and their basis for making the lead authors part of their Time 100 people of the year.

From TIME

The Human Genome Is Finally Fully Sequenced

Source: https://time.com/6163452/human-genome-fully-sequenced/

 

The first human genome was mapped in 2001 as part of the Human Genome Project, but researchers knew it was neither complete nor completely accurate. Now, scientists have produced the most completely sequenced human genome to date, filling in gaps and correcting mistakes in the previous version.

The sequence is the most complete reference genome for any mammal so far. The findings from six new papers describing the genome, which were published in Science, should lead to a deeper understanding of human evolution and potentially reveal new targets for addressing a host of diseases.

A more precise human genome

“The Human Genome Project relied on DNA obtained through blood draws; that was the technology at the time,” says Adam Phillippy, head of genome informatics at the National Institutes of Health’s National Human Genome Research Institute (NHGRI) and senior author of one of the new papers. “The techniques at the time introduced errors and gaps that have persisted all of these years. It’s nice now to fill in those gaps and correct those mistakes.”

“We always knew there were parts missing, but I don’t think any of us appreciated how extensive they were, or how interesting,” says Michael Schatz, professor of computer science and biology at Johns Hopkins University and another senior author of the same paper.

The work is the result of the Telomere to Telomere consortium, which is supported by NHGRI and involves genetic and computational biology experts from dozens of institutes around the world. The group focused on filling in the 8% of the human genome that remained a genetic black hole from the first draft sequence. Since then, geneticists have been trying to add those missing portions bit by bit. The latest group of studies identifies about an entire chromosome’s worth of new sequences, representing 200 million more base pairs (the letters making up the genome) and 1,956 new genes.

 

NOTE: In 2001 many scientists postulated there were as much as 100,000 coding human genes however now we understand there are about 20,000 to 25,000 human coding genes.  This does not however take into account the multiple diversity obtained from alternate splicing, gene duplications, SNPs, and chromosomal rearrangements.

Scientists were also able to sequence the long stretches of DNA that contained repeated sequences, which genetic experts originally thought were similar to copying errors and dismissed as so-called “junk DNA”. These repeated sequences, however, may play roles in certain human diseases. “Just because a sequence is repetitive doesn’t mean it’s junk,” says Eichler. He points out that critical genes are embedded in these repeated regions—genes that contribute to machinery that creates proteins, genes that dictate how cells divide and split their DNA evenly into their two daughter cells, and human-specific genes that might distinguish the human species from our closest evolutionary relatives, the primates. In one of the papers, for example, researchers found that primates have different numbers of copies of these repeated regions than humans, and that they appear in different parts of the genome.

“These are some of the most important functions that are essential to live, and for making us human,” says Eichler. “Clearly, if you get rid of these genes, you don’t live. That’s not junk to me.”

Deciphering what these repeated sections mean, if anything, and how the sequences of previously unsequenced regions like the centromeres will translate to new therapies or better understanding of human disease, is just starting, says Deanna Church, a vice president at Inscripta, a genome engineering company who wrote a commentary accompanying the scientific articles. Having the full sequence of a human genome is different from decoding it; she notes that currently, of people with suspected genetic disorders whose genomes are sequenced, about half can be traced to specific changes in their DNA. That means much of what the human genome does still remains a mystery.

The investigators in the Telomere to Telomere Consortium made the Time 100 People of the Year.

Michael Schatz, Karen Miga, Evan Eichler, and Adam Phillippy

Illustration by Brian Lutz for Time (Source Photos: Will Kirk—Johns Hopkins University; Nick Gonzales—UC Santa Cruz; Patrick Kehoe; National Human Genome Research Institute)

BY JENNIFER DOUDNA

MAY 23, 2022 6:08 AM EDT

Ever since the draft of the human genome became available in 2001, there has been a nagging question about the genome’s “dark matter”—the parts of the map that were missed the first time through, and what they contained. Now, thanks to Adam Phillippy, Karen Miga, Evan Eichler, Michael Schatz, and the entire Telomere-to-Telomere Consortium (T2T) of scientists that they led, we can see the full map of the human genomic landscape—and there’s much to explore.

In the scientific community, there wasn’t a consensus that mapping these missing parts was necessary. Some in the field felt there was already plenty to do using the data in hand. In addition, overcoming the technical challenges to getting the missing information wasn’t possible until recently. But the more we learn about the genome, the more we understand that every piece of the puzzle is meaningful.

I admire the

T2T group’s willingness to grapple with the technical demands of this project and their persistence in expanding the genome map into uncharted territory. The complete human genome sequence is an invaluable resource that may provide new insights into the origin of diseases and how we can treat them. It also offers the most complete look yet at the genetic script underlying the very nature of who we are as human beings.

Doudna is a biochemist and winner of the 2020 Nobel Prize in Chemistry

Source: https://time.com/collection/100-most-influential-people-2022/6177818/evan-eichler-karen-miga-adam-phillippy-michael-schatz/

Other articles on the Human Genome Project and Junk DNA in this Open Access Scientific Journal Include:

 

International Award for Human Genome Project

 

Cracking the Genome – Inside the Race to Unlock Human DNA – quotes in newspapers

 

The Human Genome Project

 

Junk DNA and Breast Cancer

 

A Perspective on Personalized Medicine

 

 

 

 

 

 

 

Additional References

 

1. P. Scalia, A. Giordano, C. Martini, S. J. Williams, Isoform- and Paralog-Switching in IR-Signaling: When Diabetes Opens the Gates to Cancer. Biomolecules 10, (Nov 30, 2020).

 

 

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New studies link cell cycle proteins to immunosurveillance of premalignant cells

Posted in Apoptosis, Biological Networks, Biological Networks, Gene Regulation and Evolution, Cancer - General, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer-Immune Interactions, Cell Biology, Signaling & Cell Circuits, Circulating Tumor Cells (CTC), Disease Biology, DNA repair, Efficacy of Anti-Tumor T Cells, Exosomes, Exosomes: Natural Carriers for siRNA Delivery, Immune Modulatory, Immuno-Oncology & Genomics, Immunology, KRAS Mutation, Modulating Macrophages in Cancer Immunotherapy, NK Cell-Based Cancer Immunotherapy, TP53 - Germline mutations, tagged CDKI, cell cycle, cell cycle arrest, cell cycle protein, cellular senescence, DNA repair or transcription factor genes, Immunology, immunosuppression, immunosurveillance, NF-kB, p21, p53, premalignant, transcriptional, transcriptional regulation, tumor suppressors on December 16, 2021| Leave a Comment »

New studies link cell cycle proteins to immunosurveillance of premalignant cells

Curator: Stephen J. Williams, Ph.D.

The following is from a Perspectives article in the journal Science by Virinder Reen and Jesus Gil called “Clearing Stressed Cells: Cell cycle arrest produces a p21-dependent secretome that initaites immunosurveillance of premalignant cells”. This is a synopsis of the Sturmlechener et al. research article in the same issue (2).

Complex organisms repair stress-induced damage to limit the replication of faulty cells that could drive cancer. When repair is not possible, tissue homeostasis is maintained by the activation of stress response programs such as apoptosis, which eliminates the cells, or senescence, which arrests them (1). Cellular senescence causes the arrest of damaged cells through the induction of cyclin-dependent kinase inhibitors (CDKIs) such as p16 and p21 (2). Senescent cells also produce a bioactive secretome (the senescence-associated secretory phenotype, SASP) that places cells under immunosurveillance, which is key to avoiding the detrimental inflammatory effects caused by lingering senescent cells on surrounding tissues. On page 577 of this issue, Sturmlechner et al. (3) report that induction of p21 not only contributes to the arrest of senescent cells, but is also an early signal that primes stressed cells for immunosurveillance.Senescence is a complex program that is tightly regulated at the epigenetic and transcriptional levels. For example, exit from the cell cycle is controlled by the induction of p16 and p21, which inhibit phosphorylation of the retinoblastoma protein (RB), a transcriptional regulator and tumor suppressor. Hypophosphorylated RB represses transcription of E2F target genes, which are necessary for cell cycle progression. Conversely, production of the SASP is regulated by a complex program that involves super-enhancer (SE) remodeling and activation of transcriptional regulators such as nuclear factor κB (NF-κB) or CCAAT enhancer binding protein–β (C/EBPβ) (4).

Senescence is a complex program that is tightly regulated at the epigenetic and transcriptional levels. For example, exit from the cell cycle is controlled by the induction of p16 and p21, which inhibit phosphorylation of the retinoblastoma protein (RB), a transcriptional regulator and tumor suppressor. Hypophosphorylated RB represses transcription of E2F target genes, which are necessary for cell cycle progression. Conversely, production of the SASP is regulated by a complex program that involves super-enhancer (SE) remodeling and activation of transcriptional regulators such as nuclear factor κB (NF-κB) or CCAAT enhancer binding protein–β (C/EBPβ) (4).

Sturmlechner et al. found that activation of p21 following stress rapidly halted cell cycle progression and triggered an internal biological timer (of ∼4 days in hepatocytes), allowing time to repair and resolve damage (see the figure). In parallel, C-X-C motif chemokine 14 (CXCL14), a component of the PASP, attracted macrophages to surround and closely surveil these damaged cells. Stressed cells that recovered and normalized p21 expression suspended PASP production and circumvented immunosurveillance. However, if the p21-induced stress was unmanageable, the repair timer expired, and the immune cells transitioned from surveillance to clearance mode. Adjacent macrophages mounted a cytotoxic T lymphocyte response that destroyed damaged cells. Notably, the overexpression of p21 alone was sufficient to orchestrate immune killing of stressed cells, without the need of a senescence phenotype. Overexpression of other CDKIs, such as p16 and p27, did not trigger immunosurveillance, likely because they do not induce CXCL14 expression.In the context of cancer, senescent cell clearance was first observed following reactivation of the tumor suppressor p53 in liver cancer cells. Restoring p53 signaling induced senescence and triggered the elimination of senescent cells by the innate immune system, prompting tumor regression (5). Subsequent work has revealed that the SASP alerts the immune system to target preneoplastic senescent cells. Hepatocytes expressing the oncogenic mutant NRAS^G12V (Gly¹²→Val) become senescent and secrete chemokines and cytokines that trigger CD4⁺ T cell–mediated clearance (6). Despite the relevance for tumor suppression, relatively little is known about how immunosurveillance of oncogene-induced senescent cells is initiated and controlled.

References

2. Sturmlechner I, Zhang C, Sine CC, van Deursen EJ, Jeganathan KB, Hamada N, Grasic J, Friedman D, Stutchman JT, Can I, Hamada M, Lim DY, Lee JH, Ordog T, Laberge RM, Shapiro V, Baker DJ, Li H, van Deursen JM. p21 produces a bioactive secretome that places stressed cells under immunosurveillance. Science. 2021 Oct 29;374(6567):eabb3420. doi: 10.1126/science.abb3420. Epub 2021 Oct 29. PMID: 34709885.

More Articles on Cancer, Senescence and the Immune System in this Open Access Online Scientific Journal Include

Bispecific and Trispecific Engagers: NK-T Cells and Cancer Therapy

Natural Killer Cell Response: Treatment of Cancer

Issues Need to be Resolved With ImmunoModulatory Therapies: NK cells, mAbs, and adoptive T cells

New insights in cancer, cancer immunogenesis and circulating cancer cells

Insight on Cell Senescence

Immune System Stimulants: Articles of Note @pharmaceuticalintelligence.com

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UK Biobank Makes Available 200,000 whole genomes Open Access

Posted in Big Data, Bio-Ethics, BioBanking, BioIT: BioInformatics, BioIT: BioInformatics, NGS, Clinical & Translational, Pharmaceutical R&D Informatics, Clinical Genomics, Cancer Informatics, Biological Networks, Gene Regulation and Evolution, Disease Biology, Genome Biology, Genomic Expression, Intelligent Information Systems, Personalized and Precision Medicine & Genomic Research, Population Health Management, Genetics & Pharmaceutical, tagged Amgen, biobank, biomedical, Genome-wide association study, genomics, Icelanders, NIH, Population genetics, UKBB, Whole genome sequencing on December 7, 2021| Leave a Comment »

UK Biobank Makes Available 200,000 whole genomes Open Access

Reporter: Stephen J. Williams, Ph.D.

The following is a summary of an article by Jocelyn Kaiser, published in the November 26, 2021 issue of the journal Science.

To see the full article please go to https://www.science.org/content/article/200-000-whole-genomes-made-available-biomedical-studies-uk-effort

The UK Biobank (UKBB) this week unveiled to scientists the entire genomes of 200,000 people who are part of a long-term British health study.

The trove of genomes, each linked to anonymized medical information, will allow biomedical scientists to scour the full 3 billion base pairs of human DNA for insights into the interplay of genes and health that could not be gleaned from partial sequences or scans of genome markers. “It is thrilling to see the release of this long-awaited resource,” says Stephen Glatt, a psychiatric geneticist at the State University of New York Upstate Medical University.

Other biobanks have also begun to compile vast numbers of whole genomes, 100,000 or more in some cases (see table, below). But UKBB stands out because it offers easy access to the genomic information, according to some of the more than 20,000 researchers in 90 countries who have signed up to use the data. “In terms of availability and data quality, [UKBB] surpasses all others,” says physician and statistician Omar Yaxmehen Bello-Chavolla of the National Institute for Geriatrics in Mexico City.

Enabling your vision to improve public health

Data drives discovery. We have curated a uniquely powerful biomedical database that can be accessed globally for public health research. Explore data from half a million UK Biobank participants to enable new discoveries to improve public health.

Data Showcase

Future data releases

This UKBB biobank represents genomes collected from 500,000 middle-age and elderly participants for 2006 to 2010. The genomes are mostly of a European descent. Other large scale genome sequencing ventures like Iceland’s DECODE, which collected over 100,000 genomes, is now a subsidiary of Amgen, and mostly behind IP protection, not Open Access as this database represents.

UK Biobank is a large-scale biomedical database and research resource, containing in-depth genetic and health information from half a million UK participants. The database is regularly augmented with additional data and is globally accessible to approved researchers undertaking vital research into the most common and life-threatening diseases. It is a major contributor to the advancement of modern medicine and treatment and has enabled several scientific discoveries that improve human health.

A summary of some large scale genome sequencing projects are show in the table below:

Biobank	Completed Whole Genomes	Release Information
UK Biobank	200,000	300,000 more in early 2023
TransOmics for Precision Medicien	161,000	NIH requires project specific request
Million Veterans Program	125,000	Non-Veterans Affairs researchers get first access
100,000 Genomes Project	120,000	Researchers must join Genomics England collaboration
All of Us	90,000	NIH expects to release 2022

Other Related Articles on Genome Biobank Projects in this Open Access Online Scientific Journal Include the Following:

Icelandic Population Genomic Study Results by deCODE Genetics come to Fruition: Curation of Current genomic studies

Exome Aggregation Consortium (ExAC), generated the largest catalogue so far of variation in human protein-coding regions: Sequence data of 60,000 people, NOW is a publicly accessible database

Systems Biology Analysis of Transcription Networks, Artificial Intelligence, and High-End Computing Coming to Fruition in Personalized Oncology

Diversity and Health Disparity Issues Need to be Addressed for GWAS and Precision Medicine Studies

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Defective viral RNA sensing gene OAS1 linked to severe COVID-19

Posted in Biomarkers: Inflammation, coronavirus, Coronavirus Gene Expression, COVID-19, COVID-19, Disease Biology, Mechanisms of infection by SARS-CoV-2, SARS-CoV-2, Variation in human protein-coding regions, Viral diseases, Virology - Vector-borne DIsease, Virus Infective Acute Respiratory Syndrome: SARS-CoV, tagged AAAS, COVID-19, COVID-19 SARS-CoV-2, doubled stranded RNA, OAS1, RNA, viral entry, viral infections on November 22, 2021| Leave a Comment »

Defective viral RNA sensing gene OAS1 linked to severe COVID-19

Reporter: Stephen J. Williams, Ph.D.

Source: https://www.science.org/doi/10.1126/science.abm3921

Defective viral RNA sensing linked to severe COVID-19

JOHN SCHOGGINS SCIENCE•28 Oct 2021•Vol 374, Issue 6567•pp. 535-536•DOI: 10.1126/science.abm39214,824

Why do some people with COVID-19 get sicker than others? Maybe exposure to a particularly high dose of the causative virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), accounts for the difference. Perhaps deficiencies in diet, exercise, or sleep contribute to worse illness. Although many factors govern how sick people become, a key driver of the severity of COVID-19 appears to be genetic, which is common for other human viruses and infectious agents (1). On page 579 of this issue, Wickenhagen et al. (2) show that susceptibility to severe COVID-19 is associated with a single-nucleotide polymorphism (SNP) in the human gene 2′-5′-oligoadenylate synthetase 1 (OAS1).The authors reasoned that SARS-CoV-2 should be inhibited by interferon-mediated antiviral responses, which are among the first cellular defense mechanisms produced in response to a viral infection. Interferons are a group of cytokines that induce the transcription of a large cadre of genes, many of which encode proteins with the potential to directly inhibit the invading virus. Wickenhagen et al. interrogated many hundreds of these putative antiviral proteins for their ability to suppress SARS-CoV-2 in cultured cells and found that OAS1 was particularly potent against SARS-CoV-2.OAS1 is an enzyme that is activated in the presence of double-stranded RNA, which is scattered along an otherwise singlestranded SARS-CoV-2 genome because of an assortment of RNA hairpins and other secondary structures. Once activated, OAS1 catalyzes the polymerization of adenosine triphosphate (ATP) into a second messenger, 2′-5′-oligoadenylate. This then triggers the conversion of ribonuclease L (RNaseL) into its active form so that it can cleave viral RNA, effectively blunting viral replication (3). Wickenhagen et al. found that OAS1 is expressed in respiratory tissues of healthy donors and COVID-19 patients and that it interacts with a region of the SARS-CoV-2 genome that contains double-stranded RNA secondary structures (see the figure).OAS1 exists predominantly as two isoforms in humans—a longer isoform (p46) and a shorter version (p42). Genetic variation dictates which isoform will be expressed. In humans, p46 is expressed in people who have a SNP that causes alternative splicing of the OAS1 messenger RNA (mRNA). This results in the utilization of a terminal exon that is not used to translate p42. Thus, the carboxyl terminus of the p46 OAS1 protein contains a distinct four–amino acid motif that forms a prenylation site. Prenylation is a posttranslational modification that targets proteins to membranes. In cell culture experiments, Wickenhagen et al. showed that only OAS1 p46, but not p42, could inhibit SARS-CoV-2. However, when the prenylation site of p46 was engineered into p42, this chimeric p42 protein was able to inhibit SARS-CoV-2, which strongly implicates a role for OAS1 specifically at membranes.Why are membranes important? SARS-CoV-2, like all coronaviruses, co-opts cellular membranes at the endoplasmic reticulum to form double-membrane vesicles, in which the virus replicates its genome. Thus, membrane-bound OAS1 p46 may be specifically activated by RNA viruses that form membrane-bound vesicles for replication. Indeed, the unrelated cardiovirus A, which also forms vesicular membranous structures, was inhibited by OAS1. Conversely, other respiratory RNA viruses, such as human parainfluenza virus type 3 and human respiratory syncytial virus, which do not use membrane-tethered vesicles for replication, were not inhibited by p46.Wickenhagen et al. examined a cohort of 499 COVID-19 patients hospitalized in the UK. Whereas all patients expressed OAS1, 42.5% of them did not express the antiviral p46 isoform. These patients were statistically more likely to have severe COVID-19 (be admitted to the intensive care unit). This suggests that OAS1 is an important antiviral factor in the control of SARS-CoV-2 infection and that its inability to activate RNaseL results in prolonged infections and severe disease, although other factors likely contribute. The authors also examined animals known to harbor different coronaviruses. They found evidence for prenylated OAS1 proteins in mice, cows, and camels. Notably, horseshoe bats, which are considered a possible reservoir for SARS-related coronaviruses (4), lack a prenylation motif in their OAS1 because of genomic changes that eliminated the critical four-amino acid motif. A horseshoe bat (Rhinolophus ferrumequinum) OAS1 was unable to inhibit SARS-CoV-2 infection in cell culture. Conversely, the black flying fox (Pteropus alecto)—a pteropid bat that is a reservoir for the Nipah and Hendra viruses, which can also infect humans—possesses a prenylated OAS1 that can inhibit SARS-CoV-2. These findings indicate that horseshoe bats may be genetically and evolutionarily primed to be optimal reservoir hosts for certain coronaviruses, like SARS-CoV-2.Other studies have now shown that the p46 OAS1 variant, which resides in a genomic locus inherited from Neanderthals (5–7), correlates with protection from COVID-19 severity in various populations (8, 9). These findings mirror previous studies indicating that outcomes with West Nile virus (10) and hepatitis C virus (11) infection, both of which also use membrane vesicles for replication, are also associated with genetic variation at the human OAS1 locus. Another elegant functional study complements the findings of Wickenhagen et al. by also demonstrating that prenylated OAS1 inhibits multiple viruses, including SARS-CoV-2, and is associated with protection from severe COVID-19 in patients (12).There is a growing body of evidence that provides critical understanding of how human genetic variation shapes the outcome of infectious diseases like COVID-19. In addition to OAS1, genetic variation in another viral RNA sensor, Toll-like receptor 7 (TLR7), is associated with severe COVID-19 (13–15). The effects appear to be exclusive to males, because TLR7 is on the X chromosome, so inherited deleterious mutations in TLR7 therefore result in immune cells that fail to produce normal amounts of interferon, which correlates with more severe COVID-19. Our knowledge of the host cellular factors that control SARS-CoV-2 is rapidly increasing. These findings will undoubtedly open new avenues into SARS-CoV-2 antiviral immunity and may also be beneficial for the development of strategies to treat or prevent severe COVID-19.

References and Notes

1J. L. Casanova, Proc. Natl. Acad. Sci. U.S.A.112, E7118 (2015).GO TO REFERENCECROSSREFPUBMEDGOOGLE SCHOLAR2A. Wickenhagen et al., Science374, eabj3624 (2021).GO TO REFERENCECROSSREFPUBMEDGOOGLE SCHOLAR3H. Kristiansen, H. H. Gad, S. Eskildsen-Larsen, P. Despres, R. Hartmann, J. Interferon Cytokine Res.31, 41 (2011).GO TO REFERENCECROSSREFPUBMEDGOOGLE SCHOLAR4S. Lytras, W. Xia, J. Hughes, X. Jiang, D. L. Robertson, Science373, 968 (2021).GO TO REFERENCECROSSREFPUBMEDGOOGLE SCHOLAR5S. Zhou et al., Nat. Med.27, 659 (2021).GO TO REFERENCECROSSREFPUBMEDGOOGLE SCHOLAR6H. Zeberg, S. Pääbo, Proc. Natl. Acad. Sci. U.S.A.118, e2026309118 (2021).CROSSREFPUBMEDGOOGLE SCHOLAR7F. L. Mendez, J. C. Watkins, M. F. Hammer, Mol. Biol. Evol.30, 798 (2013).GO TO REFERENCECROSSREFPUBMEDGOOGLE SCHOLAR8A. R. Banday et al., medRxiv2021).GO TO REFERENCECROSSREFGOOGLE SCHOLAR9E. Pairo-Castineira et al., Nature591, 92 (2021).GO TO REFERENCECROSSREFPUBMEDGOOGLE SCHOLAR10J. K. Lim et al., PLOS Pathog.5, e1000321 (2009).GO TO REFERENCECROSSREFPUBMEDGOOGLE SCHOLAR11M. K. El Awady et al., J. Gastroenterol. Hepatol.26, 843 (2011).GO TO REFERENCECROSSREFPUBMEDGOOGLE SCHOLAR12F. W. Soveg et al., eLife10, e71047 (2021).GO TO REFERENCECROSSREFPUBMEDGOOGLE SCHOLAR13T. Asano et al., Sci. Immunol.6, eabl4348 (2021).GO TO REFERENCECROSSREFPUBMEDGOOGLE SCHOLAR14C. Fallerini et al., eLife10, e67569 (2021).CROSSREFPUBMEDGOOGLE SCHOLAR15C. I. van der Made et al., JAMA324, 663 (2020).GO TO REFERENCECROSSREFPUBMEDGOOGLE SCHOLAR

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