Affinage

ASB10

Ankyrin repeat and SOCS box protein 10 · UniProt Q8WXI3

Length
467 aa
Mass
50.9 kDa
Annotated
2026-06-09
19 papers in source corpus 4 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ASB10 is a substrate-recognition E3 ubiquitin ligase that controls the abundance of specific client proteins and thereby regulates tissue homeostasis in the eye, vasculature, and heart (PMID:34285210, PMID:40399264). As an E3 ligase it ubiquitylates the tumor endothelial marker TEM8, targeting it for proteasomal degradation so that loss of ASB10 elevates homeostatic TEM8 levels (PMID:34285210). In the heart, ASB10 acts in the opposite direction on a different client: it binds HSP70 and competitively blocks STUB1-mediated ubiquitination of HSP70, stabilizing HSP70 and driving inflammation and accumulation of Ser394-phosphorylated HDAC2, which together exacerbate pressure-overload cardiac hypertrophy and fibrosis (PMID:40399264). In trabecular meshwork cells ASB10 localizes to intracellular vesicles where it physically associates with HSP70 and with proteasomal (20S α4 subunit) and autophagic-lysosomal machinery, and its vesicle dynamics track autophagic flux, while ASB10 itself is not ubiquitinated (PMID:23901248); silencing ASB10 reduces aqueous humor outflow facility, and a splice-altering coding variant links ASB10 to primary open-angle glaucoma (PMID:22156576). A unified enzymatic mechanism connecting substrate selection across these tissues to a single biochemical activity has not been fully resolved in the available corpus.

Mechanistic history

Synthesis pass · year-by-year structured walk · 4 steps
  1. 2011 Medium

    Established that ASB10 is functionally required for a defined physiological process, aqueous humor outflow, and is genetically linked to glaucoma, motivating mechanistic study of an otherwise uncharacterized protein.

    Evidence siRNA silencing in perfused anterior segment organ culture with outflow facility readout; ocular tissue expression analysis; minigene/patient lymphoblast splicing assay

    PMID:22156576

    Open questions at the time
    • Did not identify the molecular activity of ASB10 or any substrate
    • Mechanism linking outflow regulation to a biochemical function unknown
    • Disease causality rests on splice alteration without protein-level mechanism
  2. 2013 Medium

    Resolved where ASB10 acts and what it binds, placing it at protein-degradation machinery and identifying HSP70 and the proteasome as partners, while showing ASB10 is not itself a degradation substrate.

    Evidence Confocal/super-resolution colocalization with proteasomal and autophagic markers, co-IP of HSP70 and 20S α4 subunit, and pharmacological autophagy/proteasome modulation in primary HTM cells

    PMID:23901248

    Open questions at the time
    • No catalytic ubiquitin-ligase activity demonstrated
    • No substrate ubiquitination shown in this system
    • Functional consequence of HSP70/proteasome association in outflow not established
  3. 2021 Medium

    Demonstrated ASB10's enzymatic identity directly, showing it is an E3 ligase that ubiquitylates TEM8 for proteasomal degradation and controls its homeostatic levels.

    Evidence In vitro ubiquitination and protein stability assays with ASB10 overexpression/knockdown and TEM8 level measurement in triple-negative breast cancer cells

    PMID:34285210

    Open questions at the time
    • Whether TEM8 is a substrate in ocular or cardiac tissue not addressed
    • SOCS-box/ankyrin domain requirements for catalysis not dissected
    • Single study, single cancer cell context
  4. 2025 High

    Defined a tissue-specific, non-degradative mechanism in which ASB10 competitively shields HSP70 from STUB1-mediated ubiquitination, and showed bidirectional in vivo control of cardiac hypertrophy through this axis.

    Evidence IP-MS and reciprocal co-IP, in vitro ubiquitination competition, adenoviral overexpression in NRVMs with HSP70 inhibition, and AAV9 overexpression and shRNA knockdown in the mouse TAC model with echocardiographic/histological and pHDAC2S394 readouts

    PMID:40399264

    Open questions at the time
    • How ASB10 acts as a ligase on TEM8 yet as a competitive protector of HSP70 from another ligase is unreconciled
    • Direct measurement of HSP70 ubiquitination kinetics in vivo not shown
    • pHDAC2S394 link is epistatic rather than fully causal

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how ASB10 selects between degradative ubiquitination (TEM8) and protective substrate shielding (HSP70), and whether a single domain architecture explains both behaviors across eye, heart, and tumor contexts.
  • No structural model of substrate engagement
  • No unified rule for substrate fate
  • Ocular substrate(s) underlying outflow regulation unidentified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 2 GO:0016740 transferase activity 1 GO:0098772 molecular function regulator activity 1
Localization
GO:0005829 cytosol 2 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-392499 Metabolism of proteins 2 R-HSA-9612973 Autophagy 2
Partners
HSP70PSMA7STUB1TEM8

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 ASB10 silencing in perfused anterior segment organ culture reduced aqueous humor outflow facility by ~50% compared with control-infected anterior segments, demonstrating a functional role for ASB10 in trabecular meshwork outflow regulation. ASB10 siRNA silencing in perfused anterior segment organ culture with outflow facility measurement Human molecular genetics Medium 22156576
2011 ASB10 mRNA and protein are strongly expressed in trabecular meshwork, retinal ganglion cells, and ciliary body, as established by expression analysis in human ocular tissues. mRNA and protein expression analysis (immunohistochemistry/RT-PCR) in human ocular tissues Human molecular genetics Medium 22156576
2011 A synonymous variant c.765C>T (Thr255Thr) in ASB10 affects an exon splice enhancer site and alters mRNA splicing in lymphoblasts of affected family members with POAG. Minigene splicing assay / mRNA analysis in patient lymphoblasts Human molecular genetics Medium 22156576
2013 ASB10 localizes to intracellular vesicular structures in human trabecular meshwork (HTM) cells and co-localizes with markers of the ubiquitin-proteasomal pathway (ubiquitin, α4 subunit of 20S proteasome) and autophagic structures (LC3, p62, HDAC6, HSP70, Rab7, LAMP1), as shown by confocal and super-resolution structured illumination microscopy. Immunofluorescence confocal microscopy and super-resolution structured illumination microscopy with multiple pathway biomarkers in primary HTM cells Molecular vision Medium 23901248
2013 ASB10 physically interacts with HSP70 and with the α4 subunit of the 20S proteasome in HTM cells, as demonstrated by co-immunoprecipitation. Co-immunoprecipitation of ASB10-transfected HTM cells Molecular vision Medium 23901248
2013 ASB10 itself is not ubiquitinated, despite its association with ubiquitin-mediated degradation pathway components in HTM cells. Co-immunoprecipitation and immunofluorescence in HTM cells (negative finding) Molecular vision Medium 23901248
2013 Treatment of HTM cells with the autophagy/proteasome inhibitor MG132 significantly increased the number of small ASB10-stained vesicles, while autophagy inhibitors (wortmannin, bafilomycin A1) decreased them, indicating ASB10 vesicle dynamics are coupled to autophagic flux. Pharmacological modulation of autophagy with MG132, wortmannin, and bafilomycin A1, followed by quantitative immunofluorescence microscopy Molecular vision Medium 23901248
2021 ASB10 functions as an E3 ubiquitin ligase that ubiquitylates TEM8 (tumor endothelial marker 8) for proteasomal degradation; ASB10 deficiency in triple-negative breast cancer results in elevated homeostatic TEM8 levels. Ubiquitination assay, protein stability assay, and overexpression/knockdown of ASB10 with TEM8 protein level measurement in breast cancer cells Nature communications Medium 34285210
2025 Asb10 binds HSP70 and competitively blocks STUB1-mediated ubiquitination and proteasomal degradation of HSP70, thereby stabilizing HSP70 protein levels and exacerbating cardiac hypertrophic growth. Immunoprecipitation-mass spectrometry and co-immunoprecipitation; adenoviral Asb10 overexpression in NRVMs; siRNA and pharmacological HSP70 inhibition; AAV9-Asb10 overexpression and shAsb10 knockdown in mouse TAC model Cell death & disease High 40399264
2025 Asb10 overexpression in vivo (AAV9-Asb10) worsens cardiac function and increases interstitial fibrosis after transverse aortic constriction (TAC), while Asb10 knockdown (AAV9-shAsb10) improves outcomes, establishing Asb10 as a pro-hypertrophic factor in pressure-overload heart failure. AAV9-mediated cardiac-specific overexpression and shRNA knockdown in mouse TAC surgical model with echocardiographic and histological assessment Cell death & disease High 40399264
2025 The pro-hypertrophic effects of Asb10 are mediated through HSP70 stabilization leading to cardiac inflammation and activation of phospho-HDAC2 at Ser394 (pHDAC2S394). siRNA and pharmacological inhibition of HSP70 in Asb10-overexpressing NRVMs; measurement of inflammatory markers and pHDAC2S394 levels Cell death & disease Medium 40399264

Source papers

Stage 0 corpus · 19 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 GLC1F, a new primary open-angle glaucoma locus, maps to 7q35-q36. Archives of ophthalmology (Chicago, Ill. : 1960) 143 10037570
2011 Variants in ASB10 are associated with open-angle glaucoma. Human molecular genetics 66 22156576
2021 TEM8 marks neovasculogenic tumor-initiating cells in triple-negative breast cancer. Nature communications 61 34285210
2007 A new locus (GLC1H) for adult-onset primary open-angle glaucoma maps to the 2p15-p16 region. Archives of ophthalmology (Chicago, Ill. : 1960) 39 17210857
2016 Identification of Rare Variants in ATP8B4 as a Risk Factor for Systemic Sclerosis by Whole-Exome Sequencing. Arthritis & rheumatology (Hoboken, N.J.) 38 26473621
2020 Epigenetics of Skeletal Muscle-Associated Genes in the ASB, LRRC, TMEM, and OSBPL Gene Families. Epigenomes 32 34968235
2013 Ankyrin repeat and suppressor of cytokine signaling box containing protein-10 is associated with ubiquitin-mediated degradation pathways in trabecular meshwork cells. Molecular vision 25 23901248
2001 Genetic linkage of autosomal dominant primary open angle glaucoma to chromosome 3q in a Greek pedigree. European journal of human genetics : EJHG 22 11436127
2012 Analysis of ASB10 variants in open angle glaucoma. Human molecular genetics 21 22798626
2003 Genetic, ophthalmic, morphometric and histopathological analysis of the Retinopathy Globe Enlarged (rge) chicken. Molecular vision 20 12847422
2018 Epigenome-Wide Analyses Identify Two Novel Associations With Recurrent Stroke in the Vitamin Intervention for Stroke Prevention Clinical Trial. Frontiers in genetics 14 30237808
2016 Working your SOCS off: The role of ASB10 and protein degradation pathways in glaucoma. Experimental eye research 14 27296073
2015 Variants in the ASB10 Gene Are Associated with Primary Open Angle Glaucoma. PloS one 10 26713451
2023 Ubiquitin proteasome system and glaucoma: A survey of genetics and molecular biology studies supporting a link with pathogenic and therapeutic relevance. Molecular aspects of medicine 9 37950974
2004 Exclusion of 14 candidate loci for primary open angle glaucoma in Finnish families. Molecular vision 9 15073581
2025 Asb10 accelerates pathological cardiac remodeling by stabilizing HSP70. Cell death & disease 3 40399264
2019 Lack of Correlation between ASB10 and Normal-tension Glaucoma in a Population from the Republic of Korea. Current eye research 3 31522561
2004 Glaucoma in Costa Rica. Initial approaches. Revista de biologia tropical 2 17361544
2004 [Genetic ground of primary open angle glaucoma]. Klinika oczna 1 15646497

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