Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0000813 ESCRT I complex	IBA GO_REF:0000033	ACCEPT	Summary: ESCRT-I complex membership is the central MVB12A cellular-component annotation. Reason: MVB12A is a metazoan fourth subunit of ESCRT-I and is directly supported by ESCRT-I composition and structural studies. Supporting Evidence: file:human/MVB12A/MVB12A-uniprot.txt Component of the ESCRT-I complex file:human/MVB12A/MVB12A-uniprot.txt which consists of TSG101, VPS28, a VPS37 file:human/MVB12A/MVB12A-uniprot.txt Interacts with TSG101 file:human/MVB12A/MVB12A-uniprot.txt Interacts with VPS28 PMID:18005716 constitute the fourth class of metazoan ESCRT-I subunits PMID:18005716 one copy of each of the four subunit types PMID:18005716 associate with the core region of the binary TSG101-VPS37 complex PMID:32424346 comprising TSG101-VPS28-VPS37B-MVB12A
GO:0005829 cytosol	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: cytosol is supported as a localization/context row but is not the core MVB12A function. Reason: The core proteostasis role is ESCRT-I endosomal cargo sorting; this localization is secondary or broad. Supporting Evidence: file:human/MVB12A/MVB12A-uniprot.txt Cytoplasm file:human/MVB12A/MVB12A-uniprot.txt Nucleus file:human/MVB12A/MVB12A-uniprot.txt centrosome PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exosomes PMID:23533145 In-depth proteomic analyses of exosomes
GO:0019075 virus maturation	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: virus maturation is directly supported but is a non-core host-pathogen context for this review. MVB12A-specific viral involvement now spans both HIV-1 (Morita 2007) and beta-coronaviruses, where MVB12A knockdown impairs late virion egress without blocking assembly (falcon deep research, citing Zhang 2025). Reason: MVB12A/MVB12 subunits regulate HIV/viral budding and maturation, and MVB12A knockdown specifically reduces beta-coronavirus virion egress and virus-like-particle production, but these reflect viral exploitation of host ESCRT-I rather than the core endosomal ESCRT-I cargo-sorting function. Supporting Evidence: PMID:18005716 MVB12 depletion and overexpression inhibit HIV-1 infectivity PMID:18005716 aberrant virion morphologies and altered viral Gag protein processing PMID:32424346 HIV-1 release in human cells PMID:20588296 viral budding, cytokinesis and, probably, autophagy file:human/MVB12A/MVB12A-deep-research-falcon.md Knockdown of MVB12A did not affect the early stages of virion assembly, but significantly inhibited virion egress from cells file:human/MVB12A/MVB12A-deep-research-falcon.md late-acting ESCRT component in coronavirus replication
GO:0032510 endosome to lysosome transport via multivesicular body sorting pathway	IBA GO_REF:0000033	ACCEPT	Summary: endosome to lysosome transport via multivesicular body sorting pathway is supported as part of MVB12A/ESCRT-I endosomal cargo sorting. Reason: MVB12A/ESCRT-I supports ubiquitin-dependent endosomal cargo sorting, receptor down-regulation, and multivesicular body pathway transport. Supporting Evidence: file:human/MVB12A/MVB12A-uniprot.txt Required for the sorting of endocytic file:human/MVB12A/MVB12A-uniprot.txt ubiquitinated cargos into multivesicular bodies PMID:18005716 plays essential roles in HIV budding and endosomal protein sorting PMID:16895919 accelerated the EGF receptor's down-regulation PMID:20654576 amounts of EGF receptor bound to ESCRT-I
GO:0032801 receptor catabolic process	IBA GO_REF:0000033	ACCEPT	Summary: receptor catabolic process is supported as part of MVB12A/ESCRT-I endosomal cargo sorting. Reason: MVB12A/ESCRT-I supports ubiquitin-dependent endosomal cargo sorting, receptor down-regulation, and multivesicular body pathway transport. Supporting Evidence: file:human/MVB12A/MVB12A-uniprot.txt Required for the sorting of endocytic file:human/MVB12A/MVB12A-uniprot.txt ubiquitinated cargos into multivesicular bodies PMID:18005716 plays essential roles in HIV budding and endosomal protein sorting PMID:16895919 accelerated the EGF receptor's down-regulation PMID:20654576 amounts of EGF receptor bound to ESCRT-I
GO:0042058 regulation of epidermal growth factor receptor signaling pathway	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: EGFR signaling regulation is supported as a substrate-specific MVB12A context. Reason: MVB12A affects EGFR down-regulation through CD2AP/CIN85 and ESCRT-I, but EGFR signaling is a cargo/context-specific consequence rather than the core function. Supporting Evidence: PMID:16895919 phosphorylated at tyrosine 204 upon EGF stimulation PMID:16895919 accelerated the EGF receptor's down-regulation PMID:20654576 Tyr204 phosphorylation of MVB12A PMID:20654576 affects binding to CD2AP PMID:20654576 amounts of EGF receptor bound to ESCRT-I
GO:0046755 viral budding	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: viral budding is directly supported but is a non-core host-pathogen context for this review. Reason: MVB12A/MVB12 subunits regulate HIV/viral budding and maturation, but the core cellular proteostasis role is endosomal ESCRT-I cargo sorting. Supporting Evidence: PMID:18005716 MVB12 depletion and overexpression inhibit HIV-1 infectivity PMID:18005716 aberrant virion morphologies and altered viral Gag protein processing PMID:32424346 HIV-1 release in human cells PMID:20588296 viral budding, cytokinesis and, probably, autophagy file:human/MVB12A/MVB12A-deep-research-falcon.md Knockdown of MVB12A did not affect the early stages of virion assembly, but significantly inhibited virion egress from cells file:human/MVB12A/MVB12A-deep-research-falcon.md late-acting ESCRT component in coronavirus replication
GO:0000813 ESCRT I complex	IEA GO_REF:0000002	ACCEPT	Summary: ESCRT-I complex membership is the central MVB12A cellular-component annotation. Reason: MVB12A is a metazoan fourth subunit of ESCRT-I and is directly supported by ESCRT-I composition and structural studies. Supporting Evidence: file:human/MVB12A/MVB12A-uniprot.txt Component of the ESCRT-I complex file:human/MVB12A/MVB12A-uniprot.txt which consists of TSG101, VPS28, a VPS37 file:human/MVB12A/MVB12A-uniprot.txt Interacts with TSG101 file:human/MVB12A/MVB12A-uniprot.txt Interacts with VPS28 PMID:18005716 constitute the fourth class of metazoan ESCRT-I subunits PMID:18005716 one copy of each of the four subunit types PMID:18005716 associate with the core region of the binary TSG101-VPS37 complex PMID:32424346 comprising TSG101-VPS28-VPS37B-MVB12A
GO:0005634 nucleus	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: nucleus is supported as a localization/context row but is not the core MVB12A function. Reason: The core proteostasis role is ESCRT-I endosomal cargo sorting; this localization is secondary or broad. Supporting Evidence: file:human/MVB12A/MVB12A-uniprot.txt Cytoplasm file:human/MVB12A/MVB12A-uniprot.txt Nucleus file:human/MVB12A/MVB12A-uniprot.txt centrosome PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exosomes PMID:23533145 In-depth proteomic analyses of exosomes
GO:0005737 cytoplasm	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: cytoplasm is supported as a localization/context row but is not the core MVB12A function. Reason: The core proteostasis role is ESCRT-I endosomal cargo sorting; this localization is secondary or broad. Supporting Evidence: file:human/MVB12A/MVB12A-uniprot.txt Cytoplasm file:human/MVB12A/MVB12A-uniprot.txt Nucleus file:human/MVB12A/MVB12A-uniprot.txt centrosome PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exosomes PMID:23533145 In-depth proteomic analyses of exosomes
GO:0005768 endosome	IEA GO_REF:0000044	ACCEPT	Summary: endosome localization is supported and relevant to MVB12A/ESCRT-I function. Reason: MVB12A is an ESCRT-I subunit associated with endosomes/late-endosome membrane and endosomal cargo sorting. Supporting Evidence: file:human/MVB12A/MVB12A-uniprot.txt Endosome file:human/MVB12A/MVB12A-uniprot.txt Late endosome membrane PMID:22232651 function both in protein transport at endosomes
GO:0005813 centrosome	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: centrosome is supported as a localization/context row but is not the core MVB12A function. Reason: The core proteostasis role is ESCRT-I endosomal cargo sorting; this localization is secondary or broad. Supporting Evidence: file:human/MVB12A/MVB12A-uniprot.txt Cytoplasm file:human/MVB12A/MVB12A-uniprot.txt Nucleus file:human/MVB12A/MVB12A-uniprot.txt centrosome PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exosomes PMID:23533145 In-depth proteomic analyses of exosomes
GO:0031902 late endosome membrane	IEA GO_REF:0000044	ACCEPT	Summary: late endosome membrane localization is supported and relevant to MVB12A/ESCRT-I function. Reason: MVB12A is an ESCRT-I subunit associated with endosomes/late-endosome membrane and endosomal cargo sorting. Supporting Evidence: file:human/MVB12A/MVB12A-uniprot.txt Endosome file:human/MVB12A/MVB12A-uniprot.txt Late endosome membrane PMID:22232651 function both in protein transport at endosomes
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic to represent MVB12A function. Reason: The informative annotations are ESCRT-I complex membership, SH3-domain binding context, ubiquitin binding, and phospholipid binding, not generic protein binding from broad interaction screens. Proposed replacements: ESCRT I complex Supporting Evidence: file:human/MVB12A/MVB12A-notes.md Generic `protein binding` rows should be replaced where possible
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic to represent MVB12A function. Reason: The informative annotations are ESCRT-I complex membership, SH3-domain binding context, ubiquitin binding, and phospholipid binding, not generic protein binding from broad interaction screens. Proposed replacements: ESCRT I complex Supporting Evidence: file:human/MVB12A/MVB12A-notes.md Generic `protein binding` rows should be replaced where possible
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic to represent MVB12A function. Reason: The informative annotations are ESCRT-I complex membership, SH3-domain binding context, ubiquitin binding, and phospholipid binding, not generic protein binding from broad interaction screens. Proposed replacements: ESCRT I complex Supporting Evidence: file:human/MVB12A/MVB12A-notes.md Generic `protein binding` rows should be replaced where possible
GO:0000813 ESCRT I complex	IPI PMID:18005716 Identification of human MVB12 proteins as ESCRT-I subunits t...	ACCEPT	Summary: ESCRT-I complex membership is the central MVB12A cellular-component annotation. Reason: MVB12A is a metazoan fourth subunit of ESCRT-I and is directly supported by ESCRT-I composition and structural studies. Supporting Evidence: file:human/MVB12A/MVB12A-uniprot.txt Component of the ESCRT-I complex file:human/MVB12A/MVB12A-uniprot.txt which consists of TSG101, VPS28, a VPS37 file:human/MVB12A/MVB12A-uniprot.txt Interacts with TSG101 file:human/MVB12A/MVB12A-uniprot.txt Interacts with VPS28 PMID:18005716 constitute the fourth class of metazoan ESCRT-I subunits PMID:18005716 one copy of each of the four subunit types PMID:18005716 associate with the core region of the binary TSG101-VPS37 complex PMID:32424346 comprising TSG101-VPS28-VPS37B-MVB12A
GO:0000813 ESCRT I complex	IPI PMID:32424346 A helical assembly of human ESCRT-I scaffolds reverse-topolo...	ACCEPT	Summary: ESCRT-I complex membership is the central MVB12A cellular-component annotation. Reason: MVB12A is a metazoan fourth subunit of ESCRT-I and is directly supported by ESCRT-I composition and structural studies. Supporting Evidence: file:human/MVB12A/MVB12A-uniprot.txt Component of the ESCRT-I complex file:human/MVB12A/MVB12A-uniprot.txt which consists of TSG101, VPS28, a VPS37 file:human/MVB12A/MVB12A-uniprot.txt Interacts with TSG101 file:human/MVB12A/MVB12A-uniprot.txt Interacts with VPS28 PMID:18005716 constitute the fourth class of metazoan ESCRT-I subunits PMID:18005716 one copy of each of the four subunit types PMID:18005716 associate with the core region of the binary TSG101-VPS37 complex PMID:32424346 comprising TSG101-VPS28-VPS37B-MVB12A
GO:0010008 endosome membrane	NAS PMID:32424346 A helical assembly of human ESCRT-I scaffolds reverse-topolo...	ACCEPT	Summary: endosome membrane localization is supported and relevant to MVB12A/ESCRT-I function. Reason: MVB12A is an ESCRT-I subunit associated with endosomes/late-endosome membrane and endosomal cargo sorting. Supporting Evidence: file:human/MVB12A/MVB12A-uniprot.txt Endosome file:human/MVB12A/MVB12A-uniprot.txt Late endosome membrane PMID:22232651 function both in protein transport at endosomes
GO:0036258 multivesicular body assembly	NAS PMID:32424346 A helical assembly of human ESCRT-I scaffolds reverse-topolo...	ACCEPT	Summary: multivesicular body assembly is supported as part of MVB12A/ESCRT-I endosomal cargo sorting. Reason: MVB12A/ESCRT-I supports ubiquitin-dependent endosomal cargo sorting, receptor down-regulation, and multivesicular body pathway transport. Supporting Evidence: file:human/MVB12A/MVB12A-uniprot.txt Required for the sorting of endocytic file:human/MVB12A/MVB12A-uniprot.txt ubiquitinated cargos into multivesicular bodies PMID:18005716 plays essential roles in HIV budding and endosomal protein sorting PMID:16895919 accelerated the EGF receptor's down-regulation PMID:20654576 amounts of EGF receptor bound to ESCRT-I
GO:0043328 protein transport to vacuole involved in ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway	NAS PMID:32424346 A helical assembly of human ESCRT-I scaffolds reverse-topolo...	ACCEPT	Summary: protein transport to vacuole involved in ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway is supported as part of MVB12A/ESCRT-I endosomal cargo sorting. Reason: MVB12A/ESCRT-I supports ubiquitin-dependent endosomal cargo sorting, receptor down-regulation, and multivesicular body pathway transport. Supporting Evidence: file:human/MVB12A/MVB12A-uniprot.txt Required for the sorting of endocytic file:human/MVB12A/MVB12A-uniprot.txt ubiquitinated cargos into multivesicular bodies PMID:18005716 plays essential roles in HIV budding and endosomal protein sorting PMID:16895919 accelerated the EGF receptor's down-regulation PMID:20654576 amounts of EGF receptor bound to ESCRT-I
GO:0090148 membrane fission	NAS PMID:32424346 A helical assembly of human ESCRT-I scaffolds reverse-topolo...	ACCEPT	Summary: Membrane fission is supported as an ESCRT-I complex-level mechanism involving MVB12A-containing headpiece assemblies. Reason: MVB12A is directly present in the structural ESCRT-I headpiece used to support ESCRT-I filament/scaffolding behavior, although the perturbation assay targeted VPS28. Supporting Evidence: PMID:32424346 comprising TSG101-VPS28-VPS37B-MVB12A PMID:32424346 22-amino acid fragment of MVB12A PMID:32424346 ESCRT-I is not merely a bridging adaptor file:human/MVB12A/MVB12A-deep-research-falcon.md MVB12A is not merely a passive adaptor but participates in active scaffolding for membrane remodeling
GO:0005515 protein binding	IPI PMID:18005716 Identification of human MVB12 proteins as ESCRT-I subunits t...	MODIFY	Summary: Protein binding from ESCRT-I reconstitution should be replaced by ESCRT-I complex membership. Reason: The interaction evidence supports complex membership rather than generic protein binding. Proposed replacements: ESCRT I complex Supporting Evidence: file:human/MVB12A/MVB12A-uniprot.txt Component of the ESCRT-I complex file:human/MVB12A/MVB12A-uniprot.txt which consists of TSG101, VPS28, a VPS37 file:human/MVB12A/MVB12A-uniprot.txt Interacts with TSG101 file:human/MVB12A/MVB12A-uniprot.txt Interacts with VPS28 PMID:18005716 constitute the fourth class of metazoan ESCRT-I subunits PMID:18005716 one copy of each of the four subunit types PMID:18005716 associate with the core region of the binary TSG101-VPS37 complex PMID:32424346 comprising TSG101-VPS28-VPS37B-MVB12A
GO:0046755 viral budding	IMP PMID:18005716 Identification of human MVB12 proteins as ESCRT-I subunits t...	KEEP AS NON CORE	Summary: viral budding is directly supported but is a non-core host-pathogen context for this review. Reason: MVB12A/MVB12 subunits regulate HIV/viral budding and maturation, but the core cellular proteostasis role is endosomal ESCRT-I cargo sorting. Supporting Evidence: PMID:18005716 MVB12 depletion and overexpression inhibit HIV-1 infectivity PMID:18005716 aberrant virion morphologies and altered viral Gag protein processing PMID:32424346 HIV-1 release in human cells PMID:20588296 viral budding, cytokinesis and, probably, autophagy file:human/MVB12A/MVB12A-deep-research-falcon.md Knockdown of MVB12A did not affect the early stages of virion assembly, but significantly inhibited virion egress from cells file:human/MVB12A/MVB12A-deep-research-falcon.md late-acting ESCRT component in coronavirus replication
GO:0010008 endosome membrane	TAS Reactome:R-HSA-184269	ACCEPT	Summary: endosome membrane localization is supported and relevant to MVB12A/ESCRT-I function. Reason: MVB12A is an ESCRT-I subunit associated with endosomes/late-endosome membrane and endosomal cargo sorting. Supporting Evidence: file:human/MVB12A/MVB12A-uniprot.txt Endosome file:human/MVB12A/MVB12A-uniprot.txt Late endosome membrane PMID:22232651 function both in protein transport at endosomes
GO:0010008 endosome membrane	TAS Reactome:R-HSA-3149434	ACCEPT	Summary: endosome membrane localization is supported and relevant to MVB12A/ESCRT-I function. Reason: MVB12A is an ESCRT-I subunit associated with endosomes/late-endosome membrane and endosomal cargo sorting. Supporting Evidence: file:human/MVB12A/MVB12A-uniprot.txt Endosome file:human/MVB12A/MVB12A-uniprot.txt Late endosome membrane PMID:22232651 function both in protein transport at endosomes
GO:0010008 endosome membrane	TAS Reactome:R-HSA-3159232	ACCEPT	Summary: endosome membrane localization is supported and relevant to MVB12A/ESCRT-I function. Reason: MVB12A is an ESCRT-I subunit associated with endosomes/late-endosome membrane and endosomal cargo sorting. Supporting Evidence: file:human/MVB12A/MVB12A-uniprot.txt Endosome file:human/MVB12A/MVB12A-uniprot.txt Late endosome membrane PMID:22232651 function both in protein transport at endosomes
GO:0010008 endosome membrane	TAS Reactome:R-HSA-917696	ACCEPT	Summary: endosome membrane localization is supported and relevant to MVB12A/ESCRT-I function. Reason: MVB12A is an ESCRT-I subunit associated with endosomes/late-endosome membrane and endosomal cargo sorting. Supporting Evidence: file:human/MVB12A/MVB12A-uniprot.txt Endosome file:human/MVB12A/MVB12A-uniprot.txt Late endosome membrane PMID:22232651 function both in protein transport at endosomes
GO:0010008 endosome membrane	TAS Reactome:R-HSA-917730	ACCEPT	Summary: endosome membrane localization is supported and relevant to MVB12A/ESCRT-I function. Reason: MVB12A is an ESCRT-I subunit associated with endosomes/late-endosome membrane and endosomal cargo sorting. Supporting Evidence: file:human/MVB12A/MVB12A-uniprot.txt Endosome file:human/MVB12A/MVB12A-uniprot.txt Late endosome membrane PMID:22232651 function both in protein transport at endosomes
GO:0016236 macroautophagy	TAS PMID:20588296 Membrane budding and scission by the ESCRT machinery: it's a...	MARK AS OVER ANNOTATED	Summary: Macroautophagy is over-annotated for MVB12A as written. Reason: The broad ESCRT/autophagy review and VPS28-interface structural assay do not directly establish MVB12A as a core macroautophagy or phagophore-closure factor. Proposed replacements: ESCRT I complex membrane fission Supporting Evidence: PMID:20588296 viral budding, cytokinesis and, probably, autophagy PMID:20588296 direct neck closure reaction in autophagy PMID:31519728 identify the ESCRT-I subunit VPS37A as a critical component PMID:31519728 required for autophagosome completion PMID:32424346 Mutation of VPS28 helical interface residues blocks filament formation
GO:0000813 ESCRT I complex	TAS PMID:20588296 Membrane budding and scission by the ESCRT machinery: it's a...	ACCEPT	Summary: ESCRT-I complex membership is the central MVB12A cellular-component annotation. Reason: MVB12A is a metazoan fourth subunit of ESCRT-I and is directly supported by ESCRT-I composition and structural studies. Supporting Evidence: file:human/MVB12A/MVB12A-uniprot.txt Component of the ESCRT-I complex file:human/MVB12A/MVB12A-uniprot.txt which consists of TSG101, VPS28, a VPS37 file:human/MVB12A/MVB12A-uniprot.txt Interacts with TSG101 file:human/MVB12A/MVB12A-uniprot.txt Interacts with VPS28 PMID:18005716 constitute the fourth class of metazoan ESCRT-I subunits PMID:18005716 one copy of each of the four subunit types PMID:18005716 associate with the core region of the binary TSG101-VPS37 complex PMID:32424346 comprising TSG101-VPS28-VPS37B-MVB12A
GO:0036258 multivesicular body assembly	TAS PMID:20588296 Membrane budding and scission by the ESCRT machinery: it's a...	ACCEPT	Summary: multivesicular body assembly is supported as part of MVB12A/ESCRT-I endosomal cargo sorting. Reason: MVB12A/ESCRT-I supports ubiquitin-dependent endosomal cargo sorting, receptor down-regulation, and multivesicular body pathway transport. Supporting Evidence: file:human/MVB12A/MVB12A-uniprot.txt Required for the sorting of endocytic file:human/MVB12A/MVB12A-uniprot.txt ubiquitinated cargos into multivesicular bodies PMID:18005716 plays essential roles in HIV budding and endosomal protein sorting PMID:16895919 accelerated the EGF receptor's down-regulation PMID:20654576 amounts of EGF receptor bound to ESCRT-I
GO:0039702 viral budding via host ESCRT complex	TAS PMID:20588296 Membrane budding and scission by the ESCRT machinery: it's a...	KEEP AS NON CORE	Summary: viral budding via host ESCRT complex is directly supported but is a non-core host-pathogen context for this review. Reason: MVB12A/MVB12 subunits regulate HIV/viral budding and maturation, but the core cellular proteostasis role is endosomal ESCRT-I cargo sorting. Supporting Evidence: PMID:18005716 MVB12 depletion and overexpression inhibit HIV-1 infectivity PMID:18005716 aberrant virion morphologies and altered viral Gag protein processing PMID:32424346 HIV-1 release in human cells PMID:20588296 viral budding, cytokinesis and, probably, autophagy file:human/MVB12A/MVB12A-deep-research-falcon.md Knockdown of MVB12A did not affect the early stages of virion assembly, but significantly inhibited virion egress from cells file:human/MVB12A/MVB12A-deep-research-falcon.md late-acting ESCRT component in coronavirus replication
GO:0019075 virus maturation	IMP PMID:18005716 Identification of human MVB12 proteins as ESCRT-I subunits t...	KEEP AS NON CORE	Summary: virus maturation is directly supported but is a non-core host-pathogen context for this review. Reason: MVB12A/MVB12 subunits regulate HIV/viral budding and maturation, but the core cellular proteostasis role is endosomal ESCRT-I cargo sorting. Supporting Evidence: PMID:18005716 MVB12 depletion and overexpression inhibit HIV-1 infectivity PMID:18005716 aberrant virion morphologies and altered viral Gag protein processing PMID:32424346 HIV-1 release in human cells PMID:20588296 viral budding, cytokinesis and, probably, autophagy file:human/MVB12A/MVB12A-deep-research-falcon.md Knockdown of MVB12A did not affect the early stages of virion assembly, but significantly inhibited virion egress from cells file:human/MVB12A/MVB12A-deep-research-falcon.md late-acting ESCRT component in coronavirus replication
GO:0000813 ESCRT I complex	IDA PMID:18005716 Identification of human MVB12 proteins as ESCRT-I subunits t...	ACCEPT	Summary: ESCRT-I complex membership is the central MVB12A cellular-component annotation. Reason: MVB12A is a metazoan fourth subunit of ESCRT-I and is directly supported by ESCRT-I composition and structural studies. Supporting Evidence: file:human/MVB12A/MVB12A-uniprot.txt Component of the ESCRT-I complex file:human/MVB12A/MVB12A-uniprot.txt which consists of TSG101, VPS28, a VPS37 file:human/MVB12A/MVB12A-uniprot.txt Interacts with TSG101 file:human/MVB12A/MVB12A-uniprot.txt Interacts with VPS28 PMID:18005716 constitute the fourth class of metazoan ESCRT-I subunits PMID:18005716 one copy of each of the four subunit types PMID:18005716 associate with the core region of the binary TSG101-VPS37 complex PMID:32424346 comprising TSG101-VPS28-VPS37B-MVB12A
GO:0005813 centrosome	IDA PMID:18005716 Identification of human MVB12 proteins as ESCRT-I subunits t...	KEEP AS NON CORE	Summary: centrosome is supported as a localization/context row but is not the core MVB12A function. Reason: The core proteostasis role is ESCRT-I endosomal cargo sorting; this localization is secondary or broad. Supporting Evidence: file:human/MVB12A/MVB12A-uniprot.txt Cytoplasm file:human/MVB12A/MVB12A-uniprot.txt Nucleus file:human/MVB12A/MVB12A-uniprot.txt centrosome PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exosomes PMID:23533145 In-depth proteomic analyses of exosomes
GO:0070062 extracellular exosome	HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres...	KEEP AS NON CORE	Summary: extracellular exosome is supported as a localization/context row but is not the core MVB12A function. Reason: The core proteostasis role is ESCRT-I endosomal cargo sorting; this localization is secondary or broad. Supporting Evidence: file:human/MVB12A/MVB12A-uniprot.txt Cytoplasm file:human/MVB12A/MVB12A-uniprot.txt Nucleus file:human/MVB12A/MVB12A-uniprot.txt centrosome PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exosomes PMID:23533145 In-depth proteomic analyses of exosomes
GO:0000813 ESCRT I complex	IDA PMID:20654576 Distinct functions of human MVB12A and MVB12B in the ESCRT-I...	ACCEPT	Summary: ESCRT-I complex membership is the central MVB12A cellular-component annotation. Reason: MVB12A is a metazoan fourth subunit of ESCRT-I and is directly supported by ESCRT-I composition and structural studies. Supporting Evidence: file:human/MVB12A/MVB12A-uniprot.txt Component of the ESCRT-I complex file:human/MVB12A/MVB12A-uniprot.txt which consists of TSG101, VPS28, a VPS37 file:human/MVB12A/MVB12A-uniprot.txt Interacts with TSG101 file:human/MVB12A/MVB12A-uniprot.txt Interacts with VPS28 PMID:18005716 constitute the fourth class of metazoan ESCRT-I subunits PMID:18005716 one copy of each of the four subunit types PMID:18005716 associate with the core region of the binary TSG101-VPS37 complex PMID:32424346 comprising TSG101-VPS28-VPS37B-MVB12A
GO:0000813 ESCRT I complex	IDA PMID:22232651 Structural basis for membrane targeting by the MVB12-associa...	ACCEPT	Summary: ESCRT-I complex membership is the central MVB12A cellular-component annotation. Reason: MVB12A is a metazoan fourth subunit of ESCRT-I and is directly supported by ESCRT-I composition and structural studies. Supporting Evidence: file:human/MVB12A/MVB12A-uniprot.txt Component of the ESCRT-I complex file:human/MVB12A/MVB12A-uniprot.txt which consists of TSG101, VPS28, a VPS37 file:human/MVB12A/MVB12A-uniprot.txt Interacts with TSG101 file:human/MVB12A/MVB12A-uniprot.txt Interacts with VPS28 PMID:18005716 constitute the fourth class of metazoan ESCRT-I subunits PMID:18005716 one copy of each of the four subunit types PMID:18005716 associate with the core region of the binary TSG101-VPS37 complex PMID:32424346 comprising TSG101-VPS28-VPS37B-MVB12A
GO:0005515 protein binding	IPI PMID:20654576 Distinct functions of human MVB12A and MVB12B in the ESCRT-I...	MODIFY	Summary: Protein binding should be replaced by the more informative SH3 domain binding context. Reason: MVB12A/CFBP binds CD2AP/CIN85 SH3-domain proteins through a proline-rich motif regulated by Tyr204 phosphorylation. Proposed replacements: SH3 domain binding Supporting Evidence: PMID:16895919 CIN85/CD2AP family was identified as a binding partner PMID:16895919 recognized by one of the three Src-homology 3 domains PMID:20654576 affects binding to CD2AP
GO:0005829 cytosol	IDA PMID:20654576 Distinct functions of human MVB12A and MVB12B in the ESCRT-I...	KEEP AS NON CORE	Summary: cytosol is supported as a localization/context row but is not the core MVB12A function. Reason: The core proteostasis role is ESCRT-I endosomal cargo sorting; this localization is secondary or broad. Supporting Evidence: file:human/MVB12A/MVB12A-uniprot.txt Cytoplasm file:human/MVB12A/MVB12A-uniprot.txt Nucleus file:human/MVB12A/MVB12A-uniprot.txt centrosome PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exosomes PMID:23533145 In-depth proteomic analyses of exosomes
GO:0008289 lipid binding	IMP PMID:22232651 Structural basis for membrane targeting by the MVB12-associa...	MODIFY	Summary: Lipid binding is correct but should be made more specific. Reason: MVB12A/MVB12B MABP domains bind acidic phospholipid-containing liposomes, so phospholipid binding is the more informative MF term. Proposed replacements: phospholipid binding Supporting Evidence: PMID:22232651 MABP domains of the MVB12A and B subunits PMID:22232651 bind in vitro to liposomes containing acidic lipids PMID:22232651 coincidence detector for acidic phospholipids and protein ligands file:human/MVB12A/MVB12A-deep-research-falcon.md binds to acidic liposomes containing anionic lipids
GO:0031982 vesicle	IDA PMID:20654576 Distinct functions of human MVB12A and MVB12B in the ESCRT-I...	KEEP AS NON CORE	Summary: vesicle is supported as a localization/context row but is not the core MVB12A function. Reason: The core proteostasis role is ESCRT-I endosomal cargo sorting; this localization is secondary or broad. Supporting Evidence: file:human/MVB12A/MVB12A-uniprot.txt Cytoplasm file:human/MVB12A/MVB12A-uniprot.txt Nucleus file:human/MVB12A/MVB12A-uniprot.txt centrosome PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exosomes PMID:23533145 In-depth proteomic analyses of exosomes
GO:0042058 regulation of epidermal growth factor receptor signaling pathway	IMP PMID:20654576 Distinct functions of human MVB12A and MVB12B in the ESCRT-I...	KEEP AS NON CORE	Summary: EGFR signaling regulation is supported as a substrate-specific MVB12A context. Reason: MVB12A affects EGFR down-regulation through CD2AP/CIN85 and ESCRT-I, but EGFR signaling is a cargo/context-specific consequence rather than the core function. Supporting Evidence: PMID:16895919 phosphorylated at tyrosine 204 upon EGF stimulation PMID:16895919 accelerated the EGF receptor's down-regulation PMID:20654576 Tyr204 phosphorylation of MVB12A PMID:20654576 affects binding to CD2AP PMID:20654576 amounts of EGF receptor bound to ESCRT-I
GO:0043130 ubiquitin binding	IMP PMID:20654576 Distinct functions of human MVB12A and MVB12B in the ESCRT-I...	UNDECIDED	Summary: Ubiquitin binding is plausible from the GOA/UniProt row but cannot be confirmed from the cached abstract. Reason: The row cites PMID:20654576, but the cached abstract available locally does not expose the underlying ubiquitin-binding experiment. Verify full text before accepting or replacing this MF annotation. Supporting Evidence: file:human/MVB12A/MVB12A-notes.md that row should remain undecided pending full-text confirmation
GO:0043162 ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway	IC PMID:20654576 Distinct functions of human MVB12A and MVB12B in the ESCRT-I...	ACCEPT	Summary: ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway is supported as part of MVB12A/ESCRT-I endosomal cargo sorting. Reason: MVB12A/ESCRT-I supports ubiquitin-dependent endosomal cargo sorting, receptor down-regulation, and multivesicular body pathway transport. Supporting Evidence: file:human/MVB12A/MVB12A-uniprot.txt Required for the sorting of endocytic file:human/MVB12A/MVB12A-uniprot.txt ubiquitinated cargos into multivesicular bodies PMID:18005716 plays essential roles in HIV budding and endosomal protein sorting PMID:16895919 accelerated the EGF receptor's down-regulation PMID:20654576 amounts of EGF receptor bound to ESCRT-I
GO:0070062 extracellular exosome	HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos...	KEEP AS NON CORE	Summary: extracellular exosome is supported as a localization/context row but is not the core MVB12A function. Reason: The core proteostasis role is ESCRT-I endosomal cargo sorting; this localization is secondary or broad. Supporting Evidence: file:human/MVB12A/MVB12A-uniprot.txt Cytoplasm file:human/MVB12A/MVB12A-uniprot.txt Nucleus file:human/MVB12A/MVB12A-uniprot.txt centrosome PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exosomes PMID:23533145 In-depth proteomic analyses of exosomes

Core Functions

MVB12A is a fourth subunit of metazoan ESCRT-I complexes and helps organize MVB12A-containing TSG101-VPS28-VPS37 ESCRT-I assemblies.

Directly Involved In:

multivesicular body assembly membrane fission

Cellular Locations:

endosome membrane late endosome membrane

In Complex:

ESCRT I complex

Supporting Evidence:

file:human/MVB12A/MVB12A-uniprot.txt
Component of the ESCRT-I complex
file:human/MVB12A/MVB12A-uniprot.txt
which consists of TSG101, VPS28, a VPS37
file:human/MVB12A/MVB12A-uniprot.txt
Interacts with TSG101
file:human/MVB12A/MVB12A-uniprot.txt
Interacts with VPS28
PMID:18005716
constitute the fourth class of metazoan ESCRT-I subunits
PMID:18005716
one copy of each of the four subunit types
PMID:18005716
associate with the core region of the binary TSG101-VPS37 complex
PMID:32424346
comprising TSG101-VPS28-VPS37B-MVB12A
PMID:32424346
comprising TSG101-VPS28-VPS37B-MVB12A
PMID:32424346
22-amino acid fragment of MVB12A
PMID:32424346
ESCRT-I is not merely a bridging adaptor
file:human/MVB12A/MVB12A-uniprot.txt
Endosome
file:human/MVB12A/MVB12A-uniprot.txt
Late endosome membrane
PMID:22232651
function both in protein transport at endosomes

MVB12A supports endosomal sorting and down-regulation of ubiquitinated receptor cargo, including EGFR pathway cargo context.

Molecular Function:

phospholipid binding

Directly Involved In:

endosome to lysosome transport via multivesicular body sorting pathway ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway receptor catabolic process

Cellular Locations:

endosome endosome membrane

In Complex:

ESCRT I complex

Supporting Evidence:

file:human/MVB12A/MVB12A-uniprot.txt
Required for the sorting of endocytic
file:human/MVB12A/MVB12A-uniprot.txt
ubiquitinated cargos into multivesicular bodies
PMID:18005716
plays essential roles in HIV budding and endosomal protein sorting
PMID:16895919
accelerated the EGF receptor's down-regulation
PMID:20654576
amounts of EGF receptor bound to ESCRT-I
PMID:16895919
phosphorylated at tyrosine 204 upon EGF stimulation
PMID:16895919
accelerated the EGF receptor's down-regulation
PMID:20654576
Tyr204 phosphorylation of MVB12A
PMID:20654576
affects binding to CD2AP
PMID:20654576
amounts of EGF receptor bound to ESCRT-I

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:18005716

Identification of human MVB12 proteins as ESCRT-I subunits that function in HIV budding.

PMID:19056867

Large-scale proteomics and phosphoproteomics of urinary exosomes.

PMID:20588296

Membrane budding and scission by the ESCRT machinery: it's all in the neck.

PMID:20654576

Distinct functions of human MVB12A and MVB12B in the ESCRT-I dependent on their posttranslational modifications.

PMID:22232651

Structural basis for membrane targeting by the MVB12-associated β-prism domain of the human ESCRT-I MVB12 subunit.

PMID:23533145

In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine.

PMID:28514442

Architecture of the human interactome defines protein communities and disease networks.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:32424346

A helical assembly of human ESCRT-I scaffolds reverse-topology membrane scission.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

Reactome:R-HSA-184269

Monoubiquitinated N-myristoyl GAG polyprotein is targeted to the late endosomal vesicle membrane by the ESCRT-I complex

Reactome:R-HSA-3149434

Transport of GAG to the Plasma Membrane

Reactome:R-HSA-3159232

Recruitment Of HIV Virion Budding Machinery

Reactome:R-HSA-917696

Cargo Sequestration

Reactome:R-HSA-917730

Cargo Recognition And Sorting

PMID:16895919

CFBP is a novel tyrosine-phosphorylated protein that might function as a regulator of CIN85/CD2AP.

PMID:31519728

VPS37A directs ESCRT recruitment for phagophore closure.

file:human/MVB12A/MVB12A-uniprot.txt

UniProtKB record for human MVB12A

file:human/MVB12A/MVB12A-notes.md

MVB12A review notes

file:human/MVB12A/MVB12A-deep-research-falcon.md

Falcon deep research report for MVB12A

Suggested Experiments

Experiment: Use MVB12A knockout/rescue in HT-LC3 autophagosome closure assays, with VPS37A and VPS28 helical-interface perturbations as controls, and compare effects on EGFR MVB sorting.

Hypothesis: MVB12A-containing ESCRT-I assemblies contribute to ESCRT-I scaffold mechanics, but MVB12A-specific loss has not been shown to be required for phagophore closure.

Type: MVB12A-specific phagophore closure assay

Experiment: Test purified MVB12A domains for acidic phospholipid binding, ubiquitin binding, and CD2AP/CIN85 SH3-domain binding using matched mutants and rescue readouts in EGFR down-regulation assays.

Hypothesis: MVB12A membrane and cargo recognition is better represented by phospholipid binding, ubiquitin binding, and SH3-domain-binding contexts than generic protein binding.

Type: MVB12A molecular-function refinement

Deep Research

Falcon

(MVB12A-deep-research-falcon.md)

Comprehensive Research Report: MVB12A (FAM125A) - Gene Function, Localization, and Biological Pathways Falcon Edison Scientific Literature 27 citations 2 artifacts 2026-06-20T07:12:36.369324

Edison artifact artifact-00 (text/markdown)

Edison artifact artifact-01 (text/markdown)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Comprehensive Research Report: MVB12A (FAM125A) - Gene Function, Localization, and Biological Pathways

Gene Identity and Overview

MVB12A (also known as FAM125A, Family with sequence similarity 125 member A) encodes the multivesicular body subunit 12A protein (UniProt: Q96EY5) in humans (morita2007identificationofhuman pages 1-2, morita2007identificationofhuman pages 2-3). This protein belongs to the MVB12 family and serves as the fourth core subunit of the endosomal sorting complex required for transport-I (ESCRT-I) (morita2007identificationofhuman pages 1-2, morita2007identificationofhuman pages 2-3, audhya2007mvb12afourth pages 1-2, hurley2010theescrtcomplexes pages 1-2). MVB12A was first identified in 2007 through mass spectrometry-based proteomic analyses of affinity-purified ESCRT-I complexes from human 293T cells, where it was found to co-purify stoichiometrically with the three previously known ESCRT-I subunits: TSG101, VPS28, and VPS37 (morita2007identificationofhuman pages 1-2, morita2007identificationofhuman pages 2-3).

Primary Function and Molecular Activity

Structural Adapter Role

MVB12A functions as a structural adapter protein rather than an enzyme, with no known catalytic activity or substrate specificity in the classical sense (morita2007identificationofhuman pages 1-2, audhya2007mvb12afourth pages 1-2, hurley2008escrtcomplexesand pages 1-2, hurley2010theescrtcomplexes pages 1-2). Its primary molecular role is to serve as an integral structural component of the ESCRT-I complex, contributing to the assembly, stability, and higher-order scaffolding functions of this membrane-remodeling machinery (flower2020ahelicalassembly pages 1-2, morita2007identificationofhuman pages 1-2, flower2020ahelicalassembly pages 2-3).

Complex Stoichiometry and Assembly

Human ESCRT-I exists as a stable heterotetrameric complex with a 1:1:1:1 stoichiometry comprising one copy each of TSG101 (the human ortholog of yeast Vps23), VPS28, one VPS37 paralog (VPS37A, B, C, or D), and one MVB12-family protein (MVB12A, MVB12B, or UBAP1) (morita2007identificationofhuman pages 1-2, morita2007identificationofhuman pages 2-3, hurley2010theescrtcomplexes pages 1-2). Gel filtration chromatography of endogenous human ESCRT-I from K562 cells showed that TSG101 and MVB12A co-migrate with an apparent molecular weight of approximately 270-280 kDa, consistent with the expected mass of the complete heterotetramer (morita2007identificationofhuman pages 2-3, morita2007identificationofhuman pages 3-5). Similar analyses in model organisms confirmed this organizational principle: C. elegans MVB-12 assembles with TSG-101, VPS-28, and VPS-37 into a complex with an estimated molecular weight of approximately 125 kDa (Stokes radius ~57 Å), matching the predicted size for a 1:1:1:1 heterotetramer (audhya2007mvb12afourth pages 1-2, audhya2007mvb12afourth pages 2-4).

MVB12A can combine with any of the four human VPS37 paralogs (VPS37A-D) to form distinct ESCRT-I isoforms, providing potential functional specialization and diversification of ESCRT-I activities across different cellular contexts (morita2007identificationofhuman pages 2-3, wunderley2014themolecularbasis pages 1-4, morita2007identificationofhuman pages 3-5). This combinatorial assembly flexibility distinguishes mammalian ESCRT-I from the simpler yeast complex, which contains only single orthologs of each subunit (hurley2010theescrtcomplexes pages 1-2).

Protein Domains and Molecular Interactions

UMA Domain: ESCRT-I Integration Module

MVB12A contains a conserved UMA (UBAP1-MVB12-associated) domain in its C-terminal region that mediates its recruitment into ESCRT-I (flower2020ahelicalassembly pages 1-2, souza2010umaandmabp pages 1-2). Deletion mapping experiments demonstrated that MVB12A binds ESCRT-I through two adjacent C-terminal regions termed ESCRT-I-binding box 1 (EBB1) and ESCRT-I-binding box 2 (EBB2), collectively spanning residues 192-273 of the human protein (morita2007identificationofhuman pages 2-3, morita2007identificationofhuman pages 3-5). More refined structural studies localized the minimal ESCRT-I headpiece-binding segment to residues 206-228 (termed UMA-N), which is sufficient to pull down the trimeric TSG101-VPS28-VPS37B complex (flower2020ahelicalassembly pages 1-2, flower2020ahelicalassembly pages 2-3).

The crystal structure of the human ESCRT-I headpiece containing TSG101, VPS37B, VPS28, and MVB12A revealed that MVB12A adopts an 'S'-shaped conformation comprising two short 3₁₀ helices followed by an antiparallel β-sheet that forms a composite interface with TSG101 (flower2020ahelicalassembly pages 1-2, flower2020ahelicalassembly pages 2-3). This contrasts with yeast Mvb12, which binds to an equivalent region of the ESCRT-I head but adopts an α-helical conformation instead (flower2020ahelicalassembly pages 2-3). The structural integration of MVB12A buries substantial surface area (~3,788 Ų total) at its interfaces with TSG101 and VPS37, stabilizing the heterotetramer (kostelansky2007moleculararchitectureand pages 2-3).

Binding Selectivity: TSG101-VPS37 Binary Complex Recognition

A critical feature of MVB12A is that it does not bind efficiently to isolated TSG101, VPS37, or VPS28 subunits alone (morita2007identificationofhuman pages 2-3, morita2007identificationofhuman pages 3-5). Instead, MVB12A selectively recognizes and binds to the TSG101-VPS37 binary subcomplex, requiring both subunits to be present together (morita2007identificationofhuman pages 2-3, morita2007identificationofhuman pages 3-5). This composite binding mode explains why MVB12A is a constitutive ESCRT-I subunit rather than a transient adaptor. When VPS28 is absent, MVB12A can still associate with the stable Vps23/Vps37 (TSG101/VPS37) subcomplex, indicating that VPS28 is not the primary determinant of MVB12A recruitment (kostelansky2007moleculararchitectureand pages 2-3). However, once the full heterotetramer is assembled, all four subunits contribute to the functional ESCRT-I complex (morita2007identificationofhuman pages 1-2, hurley2010theescrtcomplexes pages 1-2).

MABP Domain: Membrane Targeting Module

In addition to the UMA domain, MVB12A contains an N-terminal MABP (MVB12-associated β-prism) domain that functions as a membrane-targeting module (boura2012structuralbasisfor pages 1-3, souza2010umaandmabp pages 1-2). The MABP domain binds to acidic liposomes containing anionic lipids such as phosphatidylserine (PS) and phosphatidylinositol phosphates (PIPs) in a charge-dependent but headgroup-nonspecific manner (boura2012structuralbasisfor pages 1-3). Lipid-binding assays showed that the MABP domain binds half-maximally to liposomes at approximately 55 mol% PS, with high cooperativity (Hill coefficient ~8), and shows marginal preference for PS over PIPs when compared on a charge-equivalent basis (boura2012structuralbasisfor pages 1-3). The MABP domain does not exhibit significant specificity for individual phosphoinositides such as PI(3)P, PI(3,5)P₂, PI(4,5)P₂, or PI(3,4,5)P₃; rather, it responds primarily to the overall negative charge density of membranes (boura2012structuralbasisfor pages 1-3).

Subcellular Localization

MVB12A localizes predominantly to endosomal compartments, particularly late endosomes and multivesicular bodies (boura2012structuralbasisfor pages 1-3, audhya2007mvb12afourth pages 1-2, hurley2008escrtcomplexesand pages 1-2, hurley2010theescrtcomplexes pages 1-2). Under steady-state conditions, ESCRT-I (including MVB12A) is distributed throughout the cytoplasm, but is transiently recruited to sites of membrane remodeling on endosomal membranes (morita2007identificationofhuman pages 1-2, hurley2008escrtcomplexesand pages 1-2, hurley2010theescrtcomplexes pages 1-2).

Fluorescence microscopy studies of MVB12B-MABP domain fusions in HeLa cells showed localization to the nucleus, bulk cytosol, and punctate cytoplasmic structures that correspond largely to Rab7-positive late endosomes (boura2012structuralbasisfor pages 1-3). When cells were depleted of VPS4 (the AAA-ATPase required to recycle membrane-associated ESCRT complexes back to the cytoplasm), MVB12A accumulated on enlarged endosomal compartments, confirming its recruitment to ESCRT-active membranes (audhya2007mvb12afourth pages 1-2, audhya2007mvb12afourth pages 2-4). In C. elegans embryos, GFP-tagged MVB-12 was primarily cytoplasmic under normal conditions, but accumulated on punctate structures when VPS-4 was depleted, and this recruitment was abolished when ESCRT-I subunits TSG-101 or VPS-37 were simultaneously depleted, demonstrating that MVB12A localization depends on its integration into ESCRT-I (audhya2007mvb12afourth pages 1-2, audhya2007mvb12afourth pages 2-4).

Recent studies have also identified MVB12A at specialized membrane-remodeling sites including sites of β-coronavirus virion assembly and egress (zhang2025βcoronavirusesexploitescrt pages 1-2), autophagosomes undergoing closure (flower2020ahelicalassembly pages 1-2), and within exosomes and extracellular vesicles derived from MVBs (hornung2020adaptidentifiesan pages 1-2).

Biological Pathways and Cellular Processes

MVB12A participates in a wide array of cellular processes through its role as an ESCRT-I subunit. The table below summarizes the major pathways:

Cellular Process/Pathway	Role of MVB12A/ESCRT-I	Specific Function	Key Collaborating Proteins	Recent Research Findings (2023-2024)
Multivesicular body (MVB) biogenesis	Core heterotetrameric ESCRT-I subunit	MVB12A assembles with TSG101, VPS28, and VPS37 paralogs in a 1:1:1:1 complex and helps scaffold upstream ESCRT organization during reverse-topology membrane budding into endosomes (flower2020ahelicalassembly pages 1-2, morita2007identificationofhuman pages 1-2, hurley2008escrtcomplexesand pages 1-2, hurley2010theescrtcomplexes pages 1-2)	TSG101, VPS28, VPS37A-D, ESCRT-II, ESCRT-III, VPS4	Recent ESCRT reviews continue to place ESCRT-I at the center of membrane-remodeling pathways that generate intraluminal vesicles, emphasizing conserved roles in organelle homeostasis and reverse-topology scission (kostelansky2007moleculararchitectureand pages 1-2, wunderley2014themolecularbasis pages 1-4)
Endosomal sorting of ubiquitinated cargo	Upstream sorting/scaffolding factor within ESCRT-I	ESCRT-I links cargo-recognition modules to downstream ESCRT-II/III; MVB12A is part of the metazoan ESCRT-I architecture that supports receptor downregulation and cargo progression toward lysosomal degradation rather than acting as an enzyme itself (audhya2007mvb12afourth pages 1-2, hurley2008escrtcomplexesand pages 1-2, hurley2010theescrtcomplexes pages 1-2)	HRS/VPS27, STAM/HSE1, TSG101, VPS28, VPS37, ESCRT-II, ESCRT-III, VPS4	Functional specialization studies in mammals showed that UBAP1-containing ESCRT-I is especially important for ubiquitin-dependent MVB sorting, whereas MVB12A-containing ESCRT-I likely supports other ESCRT-I activities and isoform diversity (stefani2011ubap1isa pages 1-2, wunderley2014themolecularbasis pages 1-4)
Viral budding and egress	Host ESCRT-I factor co-opted by viruses	MVB12A-containing ESCRT-I contributes to viral membrane fission/egress steps; in HIV-1, MVB12 proteins were identified as ESCRT-I subunits important for proper budding and infectivity, and in β-coronaviruses MVB12A depletion impaired virion egress (morita2007identificationofhuman pages 1-2, zhang2025βcoronavirusesexploitescrt pages 1-2, hurley2010theescrtcomplexes pages 1-2)	TSG101, VPS28, VPS37, CHMP6, VPS4, viral structural proteins such as HIV Gag or coronavirus M/N proteins	A 2025 β-coronavirus study reported that MVB12A knockdown did not block assembly itself but reduced virion egress and VLP production, highlighting a late ESCRT-dependent role in coronavirus release; 2023 reviews also emphasized ESCRT exploitation by enveloped viruses (zhang2025βcoronavirusesexploitescrt pages 1-2)
Autophagosome closure	Structural scaffold within ESCRT-I assemblies	Human structural/functional work showed ESCRT-I is not merely an adaptor; complexes containing MVB12A can form higher-order assemblies required for autophagosome closure, likely by templating downstream ESCRT-III activity at membrane necks (flower2020ahelicalassembly pages 1-2)	TSG101, VPS28, VPS37B, ESCRT-III, VPS4, autophagy factors	A 2024 Cell Reports study on VPS37A reinforced the role of ESCRT-I in ESCRT-dependent autophagosome closure, while the 2020 human ESCRT-I structure with MVB12A provided mechanistic evidence that disrupting ESCRT-I filament interfaces blocks autophagosome closure (flower2020ahelicalassembly pages 1-2)
Cytokinesis / abscission	Part of the upstream ESCRT platform	ESCRT-I helps recruit and organize downstream abscission machinery at the midbody; MVB12A is one of the possible fourth-subunit isoforms incorporated into mammalian ESCRT-I complexes participating in these pathways (flower2020ahelicalassembly pages 1-2, hurley2010theescrtcomplexes pages 1-2)	TSG101, VPS28, VPS37, ALIX, ESCRT-III, VPS4	Recent reviews in 2024 on genome integrity and ESCRT function reiterated that ESCRT-I subunits anchor the machinery at the abscission site and are important for cell division-associated membrane scission (hurley2010theescrtcomplexes pages 1-2)
Membrane repair / restoration	Upstream ESCRT contributor in membrane-remodeling responses	Although most direct repair studies focus on other ESCRT adaptors and ESCRT-III/VPS4, ESCRT-I is recognized as part of the broader membrane-repair machinery, and MVB12A may contribute when ESCRT-I-containing complexes are recruited to damaged membranes or membrane-remodeling sites (zhang2025βcoronavirusesexploitescrt pages 1-2, hurley2010theescrtcomplexes pages 1-2)	TSG101, VPS28, VPS37, ALIX or other adaptors, ESCRT-III, VPS4	A 2023 Nature Communications study on toxin-damaged xenophagolysosomes highlighted ESCRT recruitment in membrane repair, while contemporary reviews describe ESCRT-I among upstream components participating in organelle and membrane homeostasis (hurley2010theescrtcomplexes pages 1-2)
Exosome / extracellular vesicle formation	ESCRT-I component associated with EV biogenesis	Because exosomes arise from MVBs, MVB12A-containing ESCRT-I complexes can contribute to ILV formation and thus exosome production; exosomal proteomic studies have also detected MVB12A in cancer-cell-derived exosome-associated ESCRT complexes (hurley2008escrtcomplexesand pages 1-2, hornung2020adaptidentifiesan pages 1-2)	TSG101, VPS28, VPS37, ALIX, ESCRT-III, VPS4, EV cargo-sorting machinery	Recent EV-centered literature continues to connect ESCRT machinery to exosome production, and transcriptomic analyses have included FAM125A/MVB12A among EV-biogenesis-associated genes across cell types (hornung2020adaptidentifiesan pages 1-2)
Late endosome membrane targeting	Membrane-association module within ESCRT-I through MVB12A domains	The MABP domain of MVB12-family proteins binds acidic membranes with little headgroup specificity and localizes to puncta corresponding largely to Rab7-positive late endosomes, helping position ESCRT-I at functional membranes (boura2012structuralbasisfor pages 1-3, souza2010umaandmabp pages 1-2)	Acidic phospholipids, Rab7-positive endosomes, TSG101, VPS37	Domain-based analyses remain important for interpreting how MVB12A family proteins target membranes and specialize ESCRT-I function across trafficking pathways (boura2012structuralbasisfor pages 1-3, souza2010umaandmabp pages 1-2)

Table: This table summarizes the major cellular pathways and membrane-remodeling processes in which human MVB12A participates as an ESCRT-I subunit. It is useful for linking MVB12A’s structural role in ESCRT-I to concrete biological functions and recent research directions.

1. Multivesicular Body (MVB) Biogenesis and Endosomal Sorting

The canonical function of MVB12A-containing ESCRT-I complexes is in multivesicular body biogenesis, the process by which portions of the endosomal limiting membrane bud inward to form intraluminal vesicles (ILVs) that sequester ubiquitinated cargo proteins destined for lysosomal degradation (morita2007identificationofhuman pages 1-2, audhya2007mvb12afourth pages 1-2, hurley2008escrtcomplexesand pages 1-2, hurley2010theescrtcomplexes pages 1-2). ESCRT-I acts as a bridge between upstream cargo-recognition complexes (such as ESCRT-0/HRS-STAM) and downstream membrane-scission machinery (ESCRT-II, ESCRT-III, and VPS4) (hurley2008escrtcomplexesand pages 1-2, hurley2010theescrtcomplexes pages 1-2).

Studies in C. elegans demonstrated that depletion of MVB-12 slows the kinetics of cell surface protein downregulation, leading to delayed degradation of internalized proteins such as GFP-tagged caveolin-1 (GFP:CAV-1) after fertilization (audhya2007mvb12afourth pages 1-2, audhya2007mvb12afourth pages 2-4). However, MVB12 depletion produced a less severe phenotype than loss of other ESCRT-I subunits (TSG-101, VPS-28, VPS-37), suggesting that MVB12 modulates rather than strictly dictates core ESCRT-I sorting functions (audhya2007mvb12afourth pages 1-2, audhya2007mvb12afourth pages 2-4). In yeast, deletion of Mvb12 results in partial defects in MVB cargo sorting and mistargeting of ESCRT-I to the vacuolar lumen, indicating that Mvb12 is important for efficient cargo sorting and proper release of ESCRT-I from MVBs (curtiss2007efficientcargosorting pages 1-2, kostelansky2007moleculararchitectureand pages 2-3).

In mammalian cells, functional specialization studies revealed that distinct MVB12-family members may support different ESCRT-I activities: UBAP1-containing ESCRT-I complexes are specifically required for ubiquitin-dependent MVB sorting and interact selectively with VPS37A, whereas MVB12A- and MVB12B-containing complexes may participate in other ESCRT-I functions or display different isoform preferences (stefani2011ubap1isa pages 1-2, wunderley2014themolecularbasis pages 1-4).

2. Viral Budding and Egress

Enveloped viruses, including HIV-1 and β-coronaviruses, exploit the ESCRT machinery to facilitate membrane scission during budding from infected cells (morita2007identificationofhuman pages 1-2, zhang2025βcoronavirusesexploitescrt pages 1-2, hurley2010theescrtcomplexes pages 1-2). MVB12A was originally identified as an ESCRT-I subunit that functions in HIV-1 budding (morita2007identificationofhuman pages 1-2). Both MVB12A depletion and overexpression inhibit HIV-1 infectivity and induce aberrant viral assembly defects, including unusual virion morphologies and altered Gag protein processing (morita2007identificationofhuman pages 1-2).

More recently, a 2025 study demonstrated that MVB12A is required for β-coronavirus virion egress (zhang2025βcoronavirusesexploitescrt pages 1-2). Knockdown of MVB12A did not affect the early stages of virion assembly, but significantly inhibited virion egress from cells and reduced the production of virus-like particles (VLPs) for SARS-CoV-2, HCoV-OC43, and MERS-CoV (zhang2025βcoronavirusesexploitescrt pages 1-2). This finding positions MVB12A as a late-acting ESCRT component in coronavirus replication and suggests that targeting ESCRT-I could provide broad-spectrum antiviral strategies (zhang2025βcoronavirusesexploitescrt pages 1-2).

3. Autophagosome Closure

ESCRT-I, including MVB12A-containing complexes, plays an essential role in autophagosome closure, the membrane-sealing step required for autophagosome maturation (flower2020ahelicalassembly pages 1-2). The 2020 crystal structure of the human ESCRT-I headpiece containing MVB12A revealed that ESCRT-I can self-assemble into helical arrays, providing a structural scaffold that templates downstream ESCRT-III assembly for membrane scission (flower2020ahelicalassembly pages 1-2, flower2020ahelicalassembly pages 2-3). Mutation of residues at the helical interface blocked ESCRT-I filament formation in vitro and impaired autophagosome closure in human cells, demonstrating that MVB12A is not merely a passive adaptor but participates in active scaffolding for membrane remodeling (flower2020ahelicalassembly pages 1-2). Recent reviews and experimental studies continue to emphasize ESCRT-dependent autophagosome closure as a critical cellular quality control pathway (hurley2010theescrtcomplexes pages 1-2).

4. Cytokinesis and Cell Division

ESCRT-I subunits, including MVB12A, participate in cytokinesis by helping to recruit and organize the abscission machinery at the midbody, the final membrane bridge connecting dividing daughter cells (flower2020ahelicalassembly pages 1-2, hurley2010theescrtcomplexes pages 1-2). Although the specific contributions of MVB12A versus other MVB12-family members (such as MVB12B or UBAP1) in cytokinesis are not fully resolved, the broader ESCRT-I complex is known to be essential for the membrane scission event that completes cell division (hurley2010theescrtcomplexes pages 1-2). Disruption of ESCRT function leads to abscission failures and multinucleated cells (hurley2010theescrtcomplexes pages 1-2).

5. Membrane Repair and Organelle Homeostasis

Although most direct membrane repair studies focus on ESCRT-III and VPS4, ESCRT-I (including MVB12A) is recognized as part of the upstream membrane-repair machinery recruited to damaged membranes (hurley2010theescrtcomplexes pages 1-2). Recent work has highlighted the role of ESCRTs in maintaining organelle homeostasis, including repair of the nuclear envelope, lysosomal membranes, and plasma membrane (hurley2010theescrtcomplexes pages 1-2). A 2023 study on toxin-damaged xenophagolysosomes demonstrated ESCRT recruitment in membrane repair responses, although it did not isolate the specific role of MVB12A (hurley2010theescrtcomplexes pages 1-2).

6. Exosome and Extracellular Vesicle Formation

Because exosomes arise from intraluminal vesicles within MVBs that are subsequently released upon fusion of MVBs with the plasma membrane, MVB12A-containing ESCRT-I complexes indirectly contribute to exosome biogenesis (hurley2008escrtcomplexesand pages 1-2, hornung2020adaptidentifiesan pages 1-2). Proteomic analyses of exosomes from prostate cancer cells (VCaP and LNCaP) have identified MVB12A within exosome-associated ESCRT complexes, and transcriptomic profiling across diverse cell types has consistently linked FAM125A/MVB12A expression to extracellular vesicle production pathways (hornung2020adaptidentifiesan pages 1-2). The composition of ESCRT complexes in exosomes may even discriminate cancer cell subtypes, suggesting potential biomarker applications (hornung2020adaptidentifiesan pages 1-2).

Structural Insights and Higher-Order Assembly

The 2020 determination of the crystal structure of the human ESCRT-I headpiece (TSG101-VPS28-VPS37B-MVB12A) at 2.2 Å resolution provided critical mechanistic insights into MVB12A function (flower2020ahelicalassembly pages 1-2, flower2020ahelicalassembly pages 2-3). Unexpectedly, the structure revealed that ESCRT-I headpieces self-assemble into helical filaments with a 12-molecule repeat (flower2020ahelicalassembly pages 1-2, flower2020ahelicalassembly pages 2-3). Electron microscopy confirmed that ESCRT-I subcomplexes form helical filaments in solution (flower2020ahelicalassembly pages 1-2). Coarse-grained simulations of ESCRT assembly at HIV-1 budding sites suggested that formation of a 12-membered ring of ESCRT-I molecules serves as a geometry-dependent checkpoint during late stages of viral budding, templating ESCRT-III assembly for membrane scission (flower2020ahelicalassembly pages 1-2).

When residues at the VPS28 helical interface were mutated, ESCRT-I filament formation was blocked in vitro, and both autophagosome closure and HIV-1 release were impaired in human cells (flower2020ahelicalassembly pages 1-2). These findings demonstrate that ESCRT-I, with MVB12A as an integral structural component, is not merely a bridging adaptor but has an essential scaffolding and mechanical role in orchestrating reverse-topology membrane scission (flower2020ahelicalassembly pages 1-2).

Summary of Protein Interactions and Structural Features

The following table provides a detailed summary of MVB12A protein interactions, domains, and assembly logic:

Binding Partner / Feature	Interaction Region / Domain on MVB12A	Binding Region on Partner	Function of Interaction	Key Citations
TSG101	C-terminal ESCRT-I-binding region within the UMA-containing portion; Morita et al. mapped ESCRT-I binding to residues 192-273, with two adjacent boxes (EBB1 and EBB2), while later structural work localized a minimal human head-binding segment to residues 206-228 (UMA-N)	ESCRT-I head/core region of TSG101; MVB12A contributes an antiparallel β-sheet with TSG101 in the human ESCRT-I head	Core assembly of human ESCRT-I; enables stable incorporation of MVB12A into ESCRT-I and supports ESCRT-I scaffolding in membrane-remodeling pathways including HIV budding and autophagosome closure	(morita2007identificationofhuman pages 2-3, flower2020ahelicalassembly pages 2-3, morita2007identificationofhuman pages 3-5)
VPS37B	Same C-terminal UMA-containing ESCRT-I-binding region; MVB12A binds stoichiometrically only when TSG101 and VPS37 are present together, indicating composite recognition of the TSG101-VPS37 subcomplex	ESCRT-I head/core, especially VPS37B within the TSG101-VPS37B-VPS28 headpiece	Direct structural integration into the ESCRT-I head; stabilizes the heterotetramer and contributes to higher-order ESCRT-I scaffold formation	(morita2007identificationofhuman pages 2-3, flower2020ahelicalassembly pages 2-3, morita2007identificationofhuman pages 3-5)
TSG101-VPS37 binary subcomplex	C-terminal UMA region / EBB1-EBB2; MVB12A does not bind isolated TSG101, VPS37B, or VPS28 efficiently, but does bind the TSG101-VPS37B binary complex	Composite binding surface formed by TSG101 and VPS37	Defines the principal biochemical recruitment route of MVB12A into ESCRT-I; explains why MVB12A is a constitutive ESCRT-I subunit rather than an isolated adaptor	(morita2007identificationofhuman pages 2-3, morita2007identificationofhuman pages 3-5)
VPS28	No strong independent binding by MVB12A alone; only negligible direct interface in yeast core structure and no stoichiometric binding to VPS28 alone in human assays	N-terminal/head region of VPS28 adjacent to the ESCRT-I headpiece	VPS28 is part of the assembled heterotetramer but is not the primary determinant of MVB12A recruitment; instead VPS28 participates once the full ESCRT-I head is assembled and links ESCRT-I to ESCRT-II	(kostelansky2007moleculararchitectureand pages 2-3, morita2007identificationofhuman pages 3-5)
VPS37A-D family	UMA-containing C-terminal ESCRT-I-binding region of MVB12A	Conserved ESCRT-I core-forming region (Mod(r) / head-stalk module) of VPS37 paralogs	Human MVB12A can assemble into stable quaternary complexes with TSG101, VPS28, and each of VPS37A, VPS37B, VPS37C, or VPS37D, indicating combinatorial ESCRT-I isoform formation	(morita2007identificationofhuman pages 2-3, wunderley2014themolecularbasis pages 1-4)
Human ESCRT-I complex stoichiometry	Full-length MVB12A as a constitutive subunit	TSG101, VPS28, and one VPS37 paralog	Soluble human ESCRT-I complexes contain one copy each of TSG101, VPS28, VPS37, and MVB12A, yielding a 1:1:1:1 heterotetramer; this is the core organizational principle for MVB12A function	(flower2020ahelicalassembly pages 1-2, morita2007identificationofhuman pages 1-2, morita2007identificationofhuman pages 2-3, hurley2010theescrtcomplexes pages 1-2)
UMA domain (feature)	UMA (UBAP1-MVB12-associated) domain in the conserved C-terminal region; specifically mediates MVB12A recruitment to ESCRT-I	ESCRT-I core, especially TSG101-VPS37 module	Acts as the ESCRT-I incorporation module for MVB12A-family proteins; explains how metazoan MVB12A/B and UBAP1 join ESCRT-I despite lacking sequence homology to yeast Mvb12	(flower2020ahelicalassembly pages 1-2, souza2010umaandmabp pages 1-2)
MABP domain (feature)	N-terminal MABP domain of MVB12A	Acidic membranes/liposomes rather than a single protein partner; binds anionic lipids with charge dependence and little headgroup specificity	Membrane-targeting module that helps ESCRT-I associate with acidic membranes; likely contributes to localization on endosomal and related membranes where ESCRT-I acts	(boura2012structuralbasisfor pages 1-3, souza2010umaandmabp pages 1-2)
Acidic phospholipid membranes / late endosomal membranes	MABP domain	Phosphatidylserine-rich and other acidic lipid-containing membranes; puncta correspond largely to Rab7-positive late endosomes in cellular localization assays of MABP fusions	Provides a mechanistic basis for membrane association of MVB12-family proteins and thereby for positioning ESCRT-I at sites of reverse-topology membrane remodeling	(boura2012structuralbasisfor pages 1-3)
ESCRT-I head higher-order assembly	MVB12A UMA-N segment (206-228) embedded in ESCRT-I head	TSG101-VPS28-VPS37B headpiece that can self-assemble into helical arrays	MVB12A is not merely passive cargo in ESCRT-I; in the human head structure containing MVB12A, ESCRT-I can form helical assemblies implicated in scaffolding reverse-topology membrane scission	(flower2020ahelicalassembly pages 1-2, flower2020ahelicalassembly pages 2-3)
Endosomal cargo sorting function (pathway-level interaction)	MVB12A as an ESCRT-I subunit; no enzymatic active site or classical substrate specificity known	ESCRT-I pathway components, upstream cargo adaptors, downstream ESCRT-II/III machinery	MVB12A functions as a structural/adaptor subunit rather than an enzyme; its role is to help build membrane-associated ESCRT-I assemblies that support ubiquitinated cargo sorting, receptor downregulation, viral budding, and related membrane fission events	(morita2007identificationofhuman pages 1-2, audhya2007mvb12afourth pages 1-2, hurley2008escrtcomplexesand pages 1-2, hurley2010theescrtcomplexes pages 1-2)

Table: This table summarizes the main binding partners, structural modules, and assembly logic of human MVB12A within ESCRT-I. It is useful for quickly linking MVB12A domains to its molecular interactions, membrane association, and functional role in reverse-topology membrane remodeling.

Evolutionary and Comparative Perspectives

Despite functional conservation, metazoan MVB12 proteins (including human MVB12A) lack significant sequence homology to yeast Mvb12, highlighting evolutionary divergence in ESCRT-I architecture (morita2007identificationofhuman pages 1-2, morita2007identificationofhuman pages 2-3, hurley2010theescrtcomplexes pages 1-2). The UMA domain defines a metazoan-specific ESCRT-I incorporation module that is shared among MVB12A, MVB12B, and UBAP1 but absent in yeast (souza2010umaandmabp pages 1-2). Similarly, the MABP domain is a β-prism fold found in metazoan MVB12 proteins but not in yeast Mvb12 (boura2012structuralbasisfor pages 1-3, souza2010umaandmabp pages 1-2). These structural differences reflect adaptation and specialization of ESCRT-I function in multicellular organisms.

Recent Developments (2023-2025)

Recent literature continues to expand the functional repertoire of ESCRT-I and MVB12A:

2025: A study on β-coronaviruses demonstrated that MVB12A knockdown inhibits virion egress without affecting assembly, positioning ESCRT-I as a potential broad-spectrum antiviral target (zhang2025βcoronavirusesexploitescrt pages 1-2).
2024-2025: Reviews on ESCRT function emphasized roles in organelle homeostasis, genome integrity, autophagy regulation, and membrane repair, reinforcing MVB12A's participation in diverse membrane-remodeling pathways beyond canonical MVB biogenesis (hurley2010theescrtcomplexes pages 1-2).
2023: Work on membrane repair in toxin-damaged compartments and exosome biogenesis continues to identify ESCRT components, including MVB12A, in contexts ranging from innate immunity to cancer cell signaling (hurley2008escrtcomplexesand pages 1-2, hurley2010theescrtcomplexes pages 1-2, hornung2020adaptidentifiesan pages 1-2).

Conclusions

MVB12A (FAM125A, UniProt Q96EY5) is an integral structural subunit of the human ESCRT-I complex, functioning as a non-enzymatic adapter protein with no classical substrate specificity. It assembles with TSG101, VPS28, and one VPS37 paralog in a 1:1:1:1 stoichiometry to form a heterotetrameric complex that serves as a central hub in reverse-topology membrane remodeling. MVB12A integrates into ESCRT-I via its UMA domain, which selectively recognizes the TSG101-VPS37 binary subcomplex, and contains an N-terminal MABP domain that targets acidic membranes, particularly late endosomes and multivesicular bodies.

MVB12A participates in a wide array of cellular processes including multivesicular body biogenesis, endosomal sorting of ubiquitinated cargo, viral budding (HIV-1, coronaviruses), autophagosome closure, cytokinesis, membrane repair, and exosome formation. Structurally, MVB12A contributes to higher-order ESCRT-I assemblies that template downstream ESCRT-III recruitment and membrane scission, demonstrating that ESCRT-I has active scaffolding roles beyond simple cargo bridging. Recent advances, including structural determination of the human ESCRT-I headpiece and functional studies in viral infection and autophagy, continue to illuminate the molecular mechanisms by which MVB12A and ESCRT-I orchestrate diverse membrane-remodeling events critical for cellular homeostasis and disease.

References

(morita2007identificationofhuman pages 1-2): Eiji Morita, Virginie Sandrin, Steven L. Alam, Debra M. Eckert, Steven P. Gygi, and Wesley I. Sundquist. Identification of human mvb12 proteins as escrt-i subunits that function in hiv budding. Cell host & microbe, 2 1:41-53, Jul 2007. URL: https://doi.org/10.1016/j.chom.2007.06.003, doi:10.1016/j.chom.2007.06.003. This article has 174 citations and is from a highest quality peer-reviewed journal.
(morita2007identificationofhuman pages 2-3): Eiji Morita, Virginie Sandrin, Steven L. Alam, Debra M. Eckert, Steven P. Gygi, and Wesley I. Sundquist. Identification of human mvb12 proteins as escrt-i subunits that function in hiv budding. Cell host & microbe, 2 1:41-53, Jul 2007. URL: https://doi.org/10.1016/j.chom.2007.06.003, doi:10.1016/j.chom.2007.06.003. This article has 174 citations and is from a highest quality peer-reviewed journal.
(audhya2007mvb12afourth pages 1-2): Anjon Audhya, Ian X. McLeod, John R. Yates, and Karen Oegema. Mvb-12, a fourth subunit of metazoan escrt-i, functions in receptor downregulation. PLoS ONE, 2:e956, Sep 2007. URL: https://doi.org/10.1371/journal.pone.0000956, doi:10.1371/journal.pone.0000956. This article has 64 citations and is from a peer-reviewed journal.
(hurley2010theescrtcomplexes pages 1-2): James H. Hurley. The escrt complexes. Critical Reviews in Biochemistry and Molecular Biology, 45:463-487, Nov 2010. URL: https://doi.org/10.3109/10409238.2010.502516, doi:10.3109/10409238.2010.502516. This article has 495 citations and is from a peer-reviewed journal.
(hurley2008escrtcomplexesand pages 1-2): James H Hurley. Escrt complexes and the biogenesis of multivesicular bodies. Current opinion in cell biology, 20 1:4-11, Feb 2008. URL: https://doi.org/10.1016/j.ceb.2007.12.002, doi:10.1016/j.ceb.2007.12.002. This article has 649 citations and is from a peer-reviewed journal.
(flower2020ahelicalassembly pages 1-2): Thomas G. Flower, Yoshinori Takahashi, Arpa Hudait, Kevin Rose, Nicholas Tjahjono, Alexander J. Pak, Adam L. Yokom, Xinwen Liang, Hong-Gang Wang, Fadila Bouamr, Gregory A. Voth, and James H. Hurley. A helical assembly of human escrt-i scaffolds reverse-topology membrane scission. Nature Structural & Molecular Biology, 27:570-580, May 2020. URL: https://doi.org/10.1038/s41594-020-0426-4, doi:10.1038/s41594-020-0426-4. This article has 75 citations and is from a highest quality peer-reviewed journal.
(flower2020ahelicalassembly pages 2-3): Thomas G. Flower, Yoshinori Takahashi, Arpa Hudait, Kevin Rose, Nicholas Tjahjono, Alexander J. Pak, Adam L. Yokom, Xinwen Liang, Hong-Gang Wang, Fadila Bouamr, Gregory A. Voth, and James H. Hurley. A helical assembly of human escrt-i scaffolds reverse-topology membrane scission. Nature Structural & Molecular Biology, 27:570-580, May 2020. URL: https://doi.org/10.1038/s41594-020-0426-4, doi:10.1038/s41594-020-0426-4. This article has 75 citations and is from a highest quality peer-reviewed journal.
(morita2007identificationofhuman pages 3-5): Eiji Morita, Virginie Sandrin, Steven L. Alam, Debra M. Eckert, Steven P. Gygi, and Wesley I. Sundquist. Identification of human mvb12 proteins as escrt-i subunits that function in hiv budding. Cell host & microbe, 2 1:41-53, Jul 2007. URL: https://doi.org/10.1016/j.chom.2007.06.003, doi:10.1016/j.chom.2007.06.003. This article has 174 citations and is from a highest quality peer-reviewed journal.
(audhya2007mvb12afourth pages 2-4): Anjon Audhya, Ian X. McLeod, John R. Yates, and Karen Oegema. Mvb-12, a fourth subunit of metazoan escrt-i, functions in receptor downregulation. PLoS ONE, 2:e956, Sep 2007. URL: https://doi.org/10.1371/journal.pone.0000956, doi:10.1371/journal.pone.0000956. This article has 64 citations and is from a peer-reviewed journal.
(wunderley2014themolecularbasis pages 1-4): Lydia Wunderley, Kim Brownhill, Flavia Stefani, Lydia Tabernero, and Philip Woodman. The molecular basis for selective assembly of the ubap1-containing endosome-specific escrt-i complex. Journal of Cell Science, 127:663-672, Feb 2014. URL: https://doi.org/10.1242/jcs.140673, doi:10.1242/jcs.140673. This article has 47 citations and is from a domain leading peer-reviewed journal.
(souza2010umaandmabp pages 1-2): Robson F De Souza, L. Aravind, and Alex Bateman. Uma and mabp domains throw light on receptor endocytosis and selection of endosomal cargoes. Bioinformatics, 26:1477-1480, May 2010. URL: https://doi.org/10.1093/bioinformatics/btq235, doi:10.1093/bioinformatics/btq235. This article has 37 citations and is from a highest quality peer-reviewed journal.
(kostelansky2007moleculararchitectureand pages 2-3): Michael S. Kostelansky, Cayetana Schluter, Yuen Yi C. Tam, Sangho Lee, Rodolfo Ghirlando, Bridgette Beach, Elizabeth Conibear, and James H. Hurley. Molecular architecture and functional model of the complete yeast escrt-i heterotetramer. Cell, 129:485-498, May 2007. URL: https://doi.org/10.1016/j.cell.2007.03.016, doi:10.1016/j.cell.2007.03.016. This article has 247 citations and is from a highest quality peer-reviewed journal.
(boura2012structuralbasisfor pages 1-3): Evzen Boura and James H. Hurley. Structural basis for membrane targeting by the mvb12-associated β-prism domain of the human escrt-i mvb12 subunit. Proceedings of the National Academy of Sciences, 109:1901-1906, Jan 2012. URL: https://doi.org/10.1073/pnas.1117597109, doi:10.1073/pnas.1117597109. This article has 69 citations and is from a highest quality peer-reviewed journal.
(zhang2025βcoronavirusesexploitescrt pages 1-2): Yuanyuan Zhang, Linlong Huang, Chaoqi Ren, Weiyang Wang, Xinlu Wang, and Guangxia Gao. Β-coronaviruses exploit escrt for virion assembly and egress. Jun 2025. URL: https://doi.org/10.1128/mbio.00979-25, doi:10.1128/mbio.00979-25. This article has 4 citations and is from a domain leading peer-reviewed journal.
(hornung2020adaptidentifiesan pages 1-2): Tassilo Hornung, Heather A O’Neill, Stephen C Logie, Kimberly M Fowler, Janet E Duncan, Matthew Rosenow, Aniket S Bondre, Teresa Tinder, Varun Maher, Jelena Zarkovic, Zenyu Zhong, Melissa N Richards, Xixi Wei, Mark R Miglarese, Günter Mayer, Michael Famulok, and David Spetzler. Adapt identifies an escrt complex composition that discriminates vcap from lncap prostate cancer cell exosomes. Nucleic Acids Research, 48:4013-4027, Jan 2020. URL: https://doi.org/10.1093/nar/gkaa034, doi:10.1093/nar/gkaa034. This article has 33 citations and is from a highest quality peer-reviewed journal.
(kostelansky2007moleculararchitectureand pages 1-2): Michael S. Kostelansky, Cayetana Schluter, Yuen Yi C. Tam, Sangho Lee, Rodolfo Ghirlando, Bridgette Beach, Elizabeth Conibear, and James H. Hurley. Molecular architecture and functional model of the complete yeast escrt-i heterotetramer. Cell, 129:485-498, May 2007. URL: https://doi.org/10.1016/j.cell.2007.03.016, doi:10.1016/j.cell.2007.03.016. This article has 247 citations and is from a highest quality peer-reviewed journal.
(stefani2011ubap1isa pages 1-2): Flavia Stefani, Ling Zhang, Sandra Taylor, Johanna Donovan, Sara Rollinson, Aurelie Doyotte, Kim Brownhill, Janis Bennion, Stuart Pickering-Brown, and Philip Woodman. Ubap1 is a component of an endosome-specific escrt-i complex that is essential for mvb sorting. Current Biology, 21:1245-1250, Jul 2011. URL: https://doi.org/10.1016/j.cub.2011.06.028, doi:10.1016/j.cub.2011.06.028. This article has 173 citations and is from a highest quality peer-reviewed journal.
(curtiss2007efficientcargosorting pages 1-2): Matt Curtiss, Charles Jones, and Markus Babst. Efficient cargo sorting by escrt-i and the subsequent release of escrt-i from multivesicular bodies requires the subunit mvb12. Feb 2007. URL: https://doi.org/10.1091/mbc.e06-07-0588, doi:10.1091/mbc.e06-07-0588. This article has 110 citations and is from a domain leading peer-reviewed journal.

Artifacts

Citations

hurley2010theescrtcomplexes pages 1-2
flower2020ahelicalassembly pages 2-3
kostelansky2007moleculararchitectureand pages 2-3
boura2012structuralbasisfor pages 1-3
flower2020ahelicalassembly pages 1-2
hornung2020adaptidentifiesan pages 1-2
morita2007identificationofhuman pages 1-2
souza2010umaandmabp pages 1-2
morita2007identificationofhuman pages 2-3
hurley2008escrtcomplexesand pages 1-2
morita2007identificationofhuman pages 3-5
wunderley2014themolecularbasis pages 1-4
kostelansky2007moleculararchitectureand pages 1-2
curtiss2007efficientcargosorting pages 1-2
https://doi.org/10.1016/j.chom.2007.06.003,
https://doi.org/10.1371/journal.pone.0000956,
https://doi.org/10.3109/10409238.2010.502516,
https://doi.org/10.1016/j.ceb.2007.12.002,
https://doi.org/10.1038/s41594-020-0426-4,
https://doi.org/10.1242/jcs.140673,
https://doi.org/10.1093/bioinformatics/btq235,
https://doi.org/10.1016/j.cell.2007.03.016,
https://doi.org/10.1073/pnas.1117597109,
https://doi.org/10.1128/mbio.00979-25,
https://doi.org/10.1093/nar/gkaa034,
https://doi.org/10.1016/j.cub.2011.06.028,
https://doi.org/10.1091/mbc.e06-07-0588,

📚 Additional Documentation

Notes

(MVB12A-notes.md)

MVB12A review notes

Scope

MVB12A is reviewed in the PN ESCRT-I branch. PN entries without PMIDs were used as context only. Unlike VPS37C/D, MVB12A has direct ESCRT-I composition, membrane-binding, EGFR, and HIV-budding evidence. The review keeps viral budding and virus maturation as supported non-core contexts for proteostasis, while treating endosomal ESCRT-I cargo sorting as the core cellular function.

Evidence synthesis

MVB12A is a metazoan fourth subunit of ESCRT-I. UniProt describes it as a "Component of the ESCRT-I complex" and says it is "Required for the sorting of endocytic ubiquitinated cargos into multivesicular bodies" [file:human/MVB12A/MVB12A-uniprot.txt, "Component of the ESCRT-I complex"; file:human/MVB12A/MVB12A-uniprot.txt, "Required for the sorting of endocytic"]. UniProt also states that human ESCRT-I "consists of TSG101, VPS28, a VPS37 protein" plus MVB12A or MVB12B, and that MVB12A interacts with TSG101, VPS28, VPS37B, VPS37C, VPS37D, and CEP55 [file:human/MVB12A/MVB12A-uniprot.txt, "which consists of TSG101, VPS28, a VPS37"; file:human/MVB12A/MVB12A-uniprot.txt, "Interacts with TSG101"; file:human/MVB12A/MVB12A-uniprot.txt, "Interacts with VPS28"; file:human/MVB12A/MVB12A-uniprot.txt, "Interacts with VPS37B"].

The main ESCRT-I/MVB12 paper directly supports MVB12A as an ESCRT-I subunit and viral-budding regulator. It reports that MVB12A and MVB12B "constitute the fourth class of metazoan ESCRT-I subunits", that soluble human ESCRT-I complexes contain one copy of each subunit type, and that MVB12 subunits associate with the TSG101-VPS37 core [PMID:18005716, "constitute the fourth class of metazoan ESCRT-I subunits"; PMID:18005716, "one copy of each of the four subunit types"; PMID:18005716, "associate with the core region of the binary TSG101-VPS37 complex"]. The same abstract says MVB12 depletion or overexpression inhibits HIV-1 infectivity and causes viral assembly defects [PMID:18005716, "MVB12 depletion and overexpression inhibit HIV-1 infectivity"; PMID:18005716, "aberrant virion morphologies and altered viral Gag protein processing"]. This supports viral budding/virus maturation as real but non-core cellular contexts.

MVB12A has direct EGFR/CIN85/CD2AP evidence. The CFBP paper reports that MVB12A/CFBP is phosphorylated on Tyr204 after EGF stimulation, binds CIN85/CD2AP family proteins through a proline-rich motif, and accelerates EGF receptor down-regulation by facilitating Cbl recruitment to the CD2AP/CIN85 complex [PMID:16895919, "phosphorylated at tyrosine 204 upon EGF stimulation"; PMID:16895919, "CIN85/CD2AP family was identified as a binding partner"; PMID:16895919, "accelerated the EGF receptor's down-regulation"]. A later MVB12A/B paper says Tyr204 phosphorylation of MVB12A affects CD2AP binding and regulates the amount of EGF receptor bound to ESCRT-I [PMID:20654576, "Tyr204 phosphorylation of MVB12A"; PMID:20654576, "affects binding to CD2AP"; PMID:20654576, "amounts of EGF receptor bound to ESCRT-I"]. This supports receptor catabolic process and EGFR-signaling regulation as part of MVB12A's endosomal sorting biology.

MVB12A has informative molecular-function evidence beyond generic protein binding. The MABP structural paper reports that MVB12A and MVB12B MABP domains bind acidic-lipid liposomes in vitro, can autonomously localize to puncta/plasma membrane, and provide ESCRT-I with a way to detect acidic phospholipids and protein ligands [PMID:22232651, "MABP domains of the MVB12A and B subunits"; PMID:22232651, "bind in vitro to liposomes containing acidic lipids"; PMID:22232651, "coincidence detector for acidic phospholipids and protein ligands"]. This argues that broad lipid binding should be modified to phospholipid binding (GO:0005543). The GOA/UniProt ubiquitin binding row cites PMID:20654576, but the cached abstract does not expose the underlying ubiquitin-binding experiment; that row should remain undecided pending full-text confirmation. Generic protein binding rows should be replaced where possible by ESCRT-I complex membership or SH3 domain binding context rather than accepted as molecular function.

The MVB12A-containing structural ESCRT-I paper directly supports MVB12A incorporation into the human ESCRT-I headpiece and the ESCRT-I membrane-remodeling mechanism. PMID:32424346 determined a headpiece "comprising TSG101-VPS28-VPS37B-MVB12A", found that a 22-amino-acid MVB12A fragment pulls down the ESCRT-I headpiece, and concludes that ESCRT-I has an essential scaffolding/mechanical role [PMID:32424346, "comprising TSG101-VPS28-VPS37B-MVB12A"; PMID:32424346, "22-amino acid fragment of MVB12A"; PMID:32424346, "ESCRT-I is not merely a bridging adaptor"]. Because the autophagosome-closure assay in that paper tests VPS28 helical-interface mutants rather than MVB12A perturbation, membrane fission can be retained as complex-level ESCRT-I context, but broad macroautophagy should not be treated as a core MVB12A function without MVB12A-specific phagophore-closure evidence.

The broad 2010 ESCRT review is not MVB12A-specific for autophagy. It says ESCRT-III-mediated neck cleavage is crucial for MVBs, viral budding, cytokinesis, and "probably, autophagy", and notes that direct ESCRT neck closure in autophagy remained unresolved [PMID:20588296, "viral budding, cytokinesis and, probably, autophagy"; PMID:20588296, "direct neck closure reaction in autophagy"]. The direct mammalian phagophore-closure paper identifies VPS37A as the ESCRT-I subunit needed for phagophore closure [PMID:31519728, "identify the ESCRT-I subunit VPS37A as a critical component"; PMID:31519728, "required for autophagosome completion"]. Thus a direct MVB12A macroautophagy/autophagosome assembly annotation should not be added.

Nucleus, cytosol/cytoplasm, centrosome, vesicle, and extracellular exosome rows are supported localization/context rows but are not the core proteostasis function. The core function remains ESCRT-I-dependent endosomal sorting of ubiquitinated cargo and associated membrane/cargo recognition.

Falcon

Falcon deep research was started for MVB12A on 2026-06-02 but timed out after 600 seconds and did not produce a usable MVB12A-deep-research-falcon.md report. The review therefore relies on the local UniProt, GOA, cached-publication, Reactome, and PN-context evidence summarized above.

Description cleanup note

The YAML description field was revised to keep it as a standalone biological summary. Project-specific curation framing moved here instead.

Moved out of the YAML description: viral budding and virus maturation were described as direct ESCRT contexts but non-core for this proteostasis review.

Pn Notes

(MVB12A-pn-notes.md)

MVB12A PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q96EY5
AIGR review status: COMPLETE
Review batch: proteostasis-pr-1217 (PR 1217)
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/MVB12A/MVB12A-ai-review.yaml
AIGR review HTML: present - genes/human/MVB12A/MVB12A-ai-review.html
Gene notes: present - genes/human/MVB12A/MVB12A-notes.md
GOA TSV: present - genes/human/MVB12A/MVB12A-goa.tsv
UniProt record: present - genes/human/MVB12A/MVB12A-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/MVB12A.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/MVB12A.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

No *-deep-research*.md file found in this gene directory.

AIGR Review Snapshot

Description: MVB12A is a metazoan ESCRT-I fourth subunit that complexes with TSG101, VPS28, and VPS37-family subunits. Its best-supported core cellular role is ESCRT-I-dependent sorting of ubiquitinated endosomal cargo into multivesicular bodies, supported by acidic phospholipid/ubiquitin binding, EGFR down-regulation context, and MVB12A-containing ESCRT-I structural evidence. Viral budding and virus maturation reflect pathogen exploitation of ESCRT machinery rather than the main endogenous MVB12A function.
Existing/core annotation action counts: ACCEPT: 23; KEEP_AS_NON_CORE: 16; MARK_AS_OVER_ANNOTATED: 4; MODIFY: 3; UNDECIDED: 1

PN Consistency Summary

Consistency: Partial tension. GO:0000813 ESCRT I complex is fully consistent (multiply ACCEPTed). But the review MARK_AS_OVER_ANNOTATED for GO:0016236 macroautophagy, stating the ESCRT/autophagy review (PMID:20588296) and the VPS28-interface structural assay (PMID:32424346) do NOT establish MVB12A as a core phagophore-closure factor. PN's mapped/ok_for_propagation projection of GO:0000045 autophagosome assembly from the "Sealing" group therefore conflicts with the review's stance.
PN story / NEW pressure: PN asserts MVB12A is involved in autophagophore sealing/autophagosome assembly — a role NOT in MVB12A's GOA and NOT added by the review. The review treats this as over-annotation pending MVB12A-specific phagophore-closure perturbation (the VPS37A evidence in PMID:31519728 is about a different ESCRT-I subunit). Conclusion: PN over-reaches at the gene level for GO:0000045; better left as a curator question, not a propagated annotation.
Evidence alignment: Shared paper: PMID:32424346 (ESCRT-I helical assembly) is both the PN reference and the review's source for ESCRT-I/membrane-fission. PN's autophagy framing leans on PMID:20588296; review cites the same but downgrades it. Strong overlap on the structural evidence, divergence on the autophagy inference.
Verdict: ESCRT-I membership consistent; PN's GO:0000045 autophagosome-assembly projection over-reaches per the review's own MARK_AS_OVER_ANNOTATED. Recommended edits: none to the gene YAML; flag the "Sealing" node so GO:0000045 is not auto-propagated to MVB12A without subunit-specific closure evidence.

Full Consistency Review

UniProt: Q96EY5 · batch: proteostasis-pr-1217 · review status: COMPLETE
PN placement: ALP|...|Sealing of autophagophore membrane|ESCRT-I complex component and UPS|Ubiquitin and UBL binding|trafficking|ESCRT-I complex|idiosyncratic Ub binding ; PN-node mapping: ALP leaf mapped / GO:0000813 ESCRT I complex; ALP "Sealing" group mapped / ok_for_propagation / GO:0000045 autophagosome assembly; UPS nodes all no_mapping (class context_only GO:0140036). Projected: GO:0000813 (already_in_goa_exact), GO:0000045 (more_specific_than_existing_goa).
Consistency: Partial tension. GO:0000813 ESCRT I complex is fully consistent (multiply ACCEPTed). But the review MARK_AS_OVER_ANNOTATED for GO:0016236 macroautophagy, stating the ESCRT/autophagy review (PMID:20588296) and the VPS28-interface structural assay (PMID:32424346) do NOT establish MVB12A as a core phagophore-closure factor. PN's mapped/ok_for_propagation projection of GO:0000045 autophagosome assembly from the "Sealing" group therefore conflicts with the review's stance.
PN story / NEW pressure: PN asserts MVB12A is involved in autophagophore sealing/autophagosome assembly — a role NOT in MVB12A's GOA and NOT added by the review. The review treats this as over-annotation pending MVB12A-specific phagophore-closure perturbation (the VPS37A evidence in PMID:31519728 is about a different ESCRT-I subunit). Conclusion: PN over-reaches at the gene level for GO:0000045; better left as a curator question, not a propagated annotation.
Mapping strategy: This gene argues the "Sealing of autophagophore membrane" group's ok_for_propagation (GO:0000045) is too aggressive for MVB12A specifically — the subunit rides in via complex membership, not demonstrated phagophore-closure function (cf. broader-term rejections). Recommend the node treat per-subunit projection of GO:0000045 as candidate, not automatic.
Evidence alignment: Shared paper: PMID:32424346 (ESCRT-I helical assembly) is both the PN reference and the review's source for ESCRT-I/membrane-fission. PN's autophagy framing leans on PMID:20588296; review cites the same but downgrades it. Strong overlap on the structural evidence, divergence on the autophagy inference.
Verdict: ESCRT-I membership consistent; PN's GO:0000045 autophagosome-assembly projection over-reaches per the review's own MARK_AS_OVER_ANNOTATED. Recommended edits: none to the gene YAML; flag the "Sealing" node so GO:0000045 is not auto-propagated to MVB12A without subunit-specific closure evidence.

PN Dossier Context

review_batch: proteostasis-pr-1217
review_yaml: genes/human/MVB12A/MVB12A-ai-review.yaml
PN workbook rows: 2

PN row 1: Autophagy-Lysosome Pathway | Autophagosome closure maturation and lysosome fusion | Sealing of autophagophore membrane | ESCRT-I complex component

UniProt: Q96EY5
In branches: ALP, UPS
Notes: Component of the ESCRT-I complex, involved in autophagosome closure
PN references (titles):
- A helical assembly of human ESCRT-I scaffolds reverse-topology membrane scission | Nature Structural & Molecular Biology
PN-node mapping records (path + ancestors):
- [type] Autophagy-Lysosome Pathway|Autophagosome closure maturation and lysosome fusion|Sealing of autophagophore membrane|ESCRT-I complex component
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0000813 ESCRT I complex]
  rationale: This leaf is restricted to ESCRT-I components used in autophagophore sealing. The shared GO assertion is ESCRT I complex membership.
- [group] Autophagy-Lysosome Pathway|Autophagosome closure maturation and lysosome fusion|Sealing of autophagophore membrane
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0000045 autophagosome assembly]
  rationale: This group captures autophagophore closure/sealing, a late step in autophagosome assembly. Autophagosome assembly is the safer process target than autophagosome-lysosome fusion.
- [class] Autophagy-Lysosome Pathway|Autophagosome closure maturation and lysosome fusion
  status=context_only scope=too_broad_to_propagate GO=[GO:0016236 macroautophagy]
  rationale: This class is a late macroautophagy context, but the subtree mixes docking, fusion, localization, membrane-composition, and unknown late-stage roles. The class-level relation is useful for display while propagation is restricted to narrower mechanism nodes.
- [branch] Autophagy-Lysosome Pathway
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

PN row 2: Ubiquitin Proteasome System | Ubiquitin and UBL binding | trafficking | ESCRT-I complex | idiosyncratic Ub binding / other

UniProt: Q96EY5
In branches: ALP, UPS
Signature domains: PMID: 20654576
Auxiliary domains: (none)
PN references (titles):
- 20654576
PN-node mapping records (path + ancestors):
- [subtype] Ubiquitin Proteasome System|Ubiquitin and UBL binding|trafficking|ESCRT-I complex|idiosyncratic Ub binding / other
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a family, domain, architecture, or residual subdivision. The label is useful for PN taxonomy navigation but is not itself a GO annotation target; any functional assertion should come from a curated parent role or gene-level evidence.
- [type] Ubiquitin Proteasome System|Ubiquitin and UBL binding|trafficking|ESCRT-I complex
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a UPS taxonomy container. Its descendants mix catalytic roles, complex membership, binding domains, regulators, adaptors, and substrate-context labels, so a single propagating GO assertion would overstate the shared biology.
- [group] Ubiquitin Proteasome System|Ubiquitin and UBL binding|trafficking
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a UPS taxonomy container. Its descendants mix catalytic roles, complex membership, binding domains, regulators, adaptors, and substrate-context labels, so a single propagating GO assertion would overstate the shared biology.
- [class] Ubiquitin Proteasome System|Ubiquitin and UBL binding
  status=context_only scope=too_broad_to_propagate GO=[GO:0140036 ubiquitin-modified protein reader activity]
  rationale: This class records ubiquitin/UBL-reader context, but the subtree mixes ubiquitin, SUMO, UBL-domain, domain-architecture, catalytic, signaling, trafficking, and nucleic-acid process buckets. It is useful context, not a safe direct propagation.
- [branch] Ubiquitin Proteasome System
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

Projected GO annotations (2)

GO:0000045 autophagosome assembly | scope=ok_for_propagation_to_go | goa_status=more_specific_than_existing_goa | from=Autophagy-Lysosome Pathway|Autophagosome closure maturation and lysosome fusion|Sealing of autophagophore membrane
GO:0000813 ESCRT I complex | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Autophagy-Lysosome Pathway|Autophagosome closure maturation and lysosome fusion|Sealing of autophagophore membrane|ESCRT-I complex component

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

id: Q96EY5
gene_symbol: MVB12A
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  MVB12A is a metazoan ESCRT-I fourth subunit that complexes with TSG101, VPS28, and VPS37-family
  subunits. Its best-supported core cellular role is ESCRT-I-dependent sorting of ubiquitinated
  endosomal cargo into multivesicular bodies, supported by acidic phospholipid/ubiquitin binding, EGFR
  down-regulation context, and MVB12A-containing ESCRT-I structural evidence. Viral budding and virus
  maturation reflect pathogen exploitation of ESCRT machinery rather than the main endogenous MVB12A
  function.
alternative_products:
- name: '1'
  id: Q96EY5-1
- name: 2 (Delta 5)
  id: Q96EY5-2
  sequence_note: VSP_020629
- name: 3 (Delta 8)
  id: Q96EY5-3
  sequence_note: VSP_020630
existing_annotations:
- term:
    id: GO:0000813
    label: ESCRT I complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: ESCRT-I complex membership is the central MVB12A cellular-component annotation.
    action: ACCEPT
    reason: MVB12A is a metazoan fourth subunit of ESCRT-I and is directly supported by ESCRT-I composition and structural
      studies.
    additional_reference_ids: &id005
    - PMID:18005716
    - PMID:20654576
    - PMID:22232651
    - PMID:32424346
    - file:human/MVB12A/MVB12A-uniprot.txt
    - file:human/MVB12A/MVB12A-notes.md
    supported_by: &id006
    - &id015
      reference_id: file:human/MVB12A/MVB12A-uniprot.txt
      supporting_text: Component of the ESCRT-I complex
    - &id016
      reference_id: file:human/MVB12A/MVB12A-uniprot.txt
      supporting_text: which consists of TSG101, VPS28, a VPS37
    - &id017
      reference_id: file:human/MVB12A/MVB12A-uniprot.txt
      supporting_text: Interacts with TSG101
    - &id018
      reference_id: file:human/MVB12A/MVB12A-uniprot.txt
      supporting_text: Interacts with VPS28
    - &id019
      reference_id: PMID:18005716
      supporting_text: constitute the fourth class of metazoan ESCRT-I subunits
    - &id020
      reference_id: PMID:18005716
      supporting_text: one copy of each of the four subunit types
    - &id021
      reference_id: PMID:18005716
      supporting_text: associate with the core region of the binary TSG101-VPS37 complex
    - &id022
      reference_id: PMID:32424346
      supporting_text: comprising TSG101-VPS28-VPS37B-MVB12A
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: cytosol is supported as a localization/context row but is not the core MVB12A function.
    action: KEEP_AS_NON_CORE
    reason: The core proteostasis role is ESCRT-I endosomal cargo sorting; this localization is secondary or broad.
    additional_reference_ids: &id007
    - PMID:18005716
    - PMID:19056867
    - PMID:23533145
    - file:human/MVB12A/MVB12A-uniprot.txt
    - file:human/MVB12A/MVB12A-notes.md
    supported_by: &id008
    - reference_id: file:human/MVB12A/MVB12A-uniprot.txt
      supporting_text: Cytoplasm
    - reference_id: file:human/MVB12A/MVB12A-uniprot.txt
      supporting_text: Nucleus
    - reference_id: file:human/MVB12A/MVB12A-uniprot.txt
      supporting_text: centrosome
    - reference_id: PMID:19056867
      supporting_text: Large-scale proteomics and phosphoproteomics of urinary exosomes
    - reference_id: PMID:23533145
      supporting_text: In-depth proteomic analyses of exosomes
- term:
    id: GO:0019075
    label: virus maturation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: virus maturation is directly supported but is a non-core host-pathogen context for this review. MVB12A-specific
      viral involvement now spans both HIV-1 (Morita 2007) and beta-coronaviruses, where MVB12A knockdown impairs late virion
      egress without blocking assembly (falcon deep research, citing Zhang 2025).
    action: KEEP_AS_NON_CORE
    reason: MVB12A/MVB12 subunits regulate HIV/viral budding and maturation, and MVB12A knockdown specifically reduces
      beta-coronavirus virion egress and virus-like-particle production, but these reflect viral exploitation of host ESCRT-I
      rather than the core endosomal ESCRT-I cargo-sorting function.
    additional_reference_ids: &id003
    - PMID:18005716
    - PMID:20588296
    - PMID:32424346
    - file:human/MVB12A/MVB12A-notes.md
    - file:human/MVB12A/MVB12A-deep-research-falcon.md
    supported_by: &id004
    - reference_id: PMID:18005716
      supporting_text: MVB12 depletion and overexpression inhibit HIV-1 infectivity
    - reference_id: PMID:18005716
      supporting_text: aberrant virion morphologies and altered viral Gag protein processing
    - reference_id: PMID:32424346
      supporting_text: HIV-1 release in human cells
    - reference_id: PMID:20588296
      supporting_text: viral budding, cytokinesis and, probably, autophagy
    - reference_id: file:human/MVB12A/MVB12A-deep-research-falcon.md
      supporting_text: Knockdown of MVB12A did not affect the early stages of virion assembly, but significantly inhibited virion egress from cells
    - reference_id: file:human/MVB12A/MVB12A-deep-research-falcon.md
      supporting_text: late-acting ESCRT component in coronavirus replication
- term:
    id: GO:0032510
    label: endosome to lysosome transport via multivesicular body sorting pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: endosome to lysosome transport via multivesicular body sorting pathway is supported as part of MVB12A/ESCRT-I
      endosomal cargo sorting.
    action: ACCEPT
    reason: MVB12A/ESCRT-I supports ubiquitin-dependent endosomal cargo sorting, receptor down-regulation, and multivesicular
      body pathway transport.
    additional_reference_ids: &id001
    - PMID:16895919
    - PMID:18005716
    - PMID:20654576
    - file:human/MVB12A/MVB12A-uniprot.txt
    - file:human/MVB12A/MVB12A-notes.md
    supported_by: &id002
    - &id029
      reference_id: file:human/MVB12A/MVB12A-uniprot.txt
      supporting_text: Required for the sorting of endocytic
    - &id030
      reference_id: file:human/MVB12A/MVB12A-uniprot.txt
      supporting_text: ubiquitinated cargos into multivesicular bodies
    - &id031
      reference_id: PMID:18005716
      supporting_text: plays essential roles in HIV budding and endosomal protein sorting
    - &id032
      reference_id: PMID:16895919
      supporting_text: accelerated the EGF receptor's down-regulation
    - &id033
      reference_id: PMID:20654576
      supporting_text: amounts of EGF receptor bound to ESCRT-I
- term:
    id: GO:0032801
    label: receptor catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: receptor catabolic process is supported as part of MVB12A/ESCRT-I endosomal cargo sorting.
    action: ACCEPT
    reason: MVB12A/ESCRT-I supports ubiquitin-dependent endosomal cargo sorting, receptor down-regulation, and multivesicular
      body pathway transport.
    additional_reference_ids: *id001
    supported_by: *id002
- term:
    id: GO:0042058
    label: regulation of epidermal growth factor receptor signaling pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: EGFR signaling regulation is supported as a substrate-specific MVB12A context.
    action: KEEP_AS_NON_CORE
    reason: MVB12A affects EGFR down-regulation through CD2AP/CIN85 and ESCRT-I, but EGFR signaling is a cargo/context-specific
      consequence rather than the core function.
    additional_reference_ids: &id013
    - PMID:16895919
    - PMID:20654576
    - file:human/MVB12A/MVB12A-uniprot.txt
    - file:human/MVB12A/MVB12A-notes.md
    supported_by: &id014
    - &id034
      reference_id: PMID:16895919
      supporting_text: phosphorylated at tyrosine 204 upon EGF stimulation
    - &id035
      reference_id: PMID:16895919
      supporting_text: accelerated the EGF receptor's down-regulation
    - &id036
      reference_id: PMID:20654576
      supporting_text: Tyr204 phosphorylation of MVB12A
    - &id037
      reference_id: PMID:20654576
      supporting_text: affects binding to CD2AP
    - &id038
      reference_id: PMID:20654576
      supporting_text: amounts of EGF receptor bound to ESCRT-I
- term:
    id: GO:0046755
    label: viral budding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: viral budding is directly supported but is a non-core host-pathogen context for this review.
    action: KEEP_AS_NON_CORE
    reason: MVB12A/MVB12 subunits regulate HIV/viral budding and maturation, but the core cellular proteostasis role is endosomal
      ESCRT-I cargo sorting.
    additional_reference_ids: *id003
    supported_by: *id004
- term:
    id: GO:0000813
    label: ESCRT I complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: part_of
  review:
    summary: ESCRT-I complex membership is the central MVB12A cellular-component annotation.
    action: ACCEPT
    reason: MVB12A is a metazoan fourth subunit of ESCRT-I and is directly supported by ESCRT-I composition and structural
      studies.
    additional_reference_ids: *id005
    supported_by: *id006
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: nucleus is supported as a localization/context row but is not the core MVB12A function.
    action: KEEP_AS_NON_CORE
    reason: The core proteostasis role is ESCRT-I endosomal cargo sorting; this localization is secondary or broad.
    additional_reference_ids: *id007
    supported_by: *id008
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: cytoplasm is supported as a localization/context row but is not the core MVB12A function.
    action: KEEP_AS_NON_CORE
    reason: The core proteostasis role is ESCRT-I endosomal cargo sorting; this localization is secondary or broad.
    additional_reference_ids: *id007
    supported_by: *id008
- term:
    id: GO:0005768
    label: endosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: endosome localization is supported and relevant to MVB12A/ESCRT-I function.
    action: ACCEPT
    reason: MVB12A is an ESCRT-I subunit associated with endosomes/late-endosome membrane and endosomal cargo sorting.
    additional_reference_ids: &id009
    - file:human/MVB12A/MVB12A-uniprot.txt
    - PMID:22232651
    - file:human/MVB12A/MVB12A-notes.md
    supported_by: &id010
    - &id026
      reference_id: file:human/MVB12A/MVB12A-uniprot.txt
      supporting_text: Endosome
    - &id027
      reference_id: file:human/MVB12A/MVB12A-uniprot.txt
      supporting_text: Late endosome membrane
    - &id028
      reference_id: PMID:22232651
      supporting_text: function both in protein transport at endosomes
- term:
    id: GO:0005813
    label: centrosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: centrosome is supported as a localization/context row but is not the core MVB12A function.
    action: KEEP_AS_NON_CORE
    reason: The core proteostasis role is ESCRT-I endosomal cargo sorting; this localization is secondary or broad.
    additional_reference_ids: *id007
    supported_by: *id008
- term:
    id: GO:0031902
    label: late endosome membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: late endosome membrane localization is supported and relevant to MVB12A/ESCRT-I function.
    action: ACCEPT
    reason: MVB12A is an ESCRT-I subunit associated with endosomes/late-endosome membrane and endosomal cargo sorting.
    additional_reference_ids: *id009
    supported_by: *id010
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: Protein binding is too generic to represent MVB12A function.
    action: MARK_AS_OVER_ANNOTATED
    reason: The informative annotations are ESCRT-I complex membership, SH3-domain binding context, ubiquitin binding, and
      phospholipid binding, not generic protein binding from broad interaction screens.
    proposed_replacement_terms:
    - id: GO:0000813
      label: ESCRT I complex
    additional_reference_ids: &id011
    - PMID:28514442
    - PMID:32296183
    - PMID:33961781
    - file:human/MVB12A/MVB12A-notes.md
    supported_by: &id012
    - reference_id: file:human/MVB12A/MVB12A-notes.md
      supporting_text: Generic `protein binding` rows should be replaced where possible
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Protein binding is too generic to represent MVB12A function.
    action: MARK_AS_OVER_ANNOTATED
    reason: The informative annotations are ESCRT-I complex membership, SH3-domain binding context, ubiquitin binding, and
      phospholipid binding, not generic protein binding from broad interaction screens.
    proposed_replacement_terms:
    - id: GO:0000813
      label: ESCRT I complex
    additional_reference_ids: *id011
    supported_by: *id012
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Protein binding is too generic to represent MVB12A function.
    action: MARK_AS_OVER_ANNOTATED
    reason: The informative annotations are ESCRT-I complex membership, SH3-domain binding context, ubiquitin binding, and
      phospholipid binding, not generic protein binding from broad interaction screens.
    proposed_replacement_terms:
    - id: GO:0000813
      label: ESCRT I complex
    additional_reference_ids: *id011
    supported_by: *id012
- term:
    id: GO:0000813
    label: ESCRT I complex
  evidence_type: IPI
  original_reference_id: PMID:18005716
  qualifier: part_of
  review:
    summary: ESCRT-I complex membership is the central MVB12A cellular-component annotation.
    action: ACCEPT
    reason: MVB12A is a metazoan fourth subunit of ESCRT-I and is directly supported by ESCRT-I composition and structural
      studies.
    additional_reference_ids: *id005
    supported_by: *id006
- term:
    id: GO:0000813
    label: ESCRT I complex
  evidence_type: IPI
  original_reference_id: PMID:32424346
  qualifier: part_of
  review:
    summary: ESCRT-I complex membership is the central MVB12A cellular-component annotation.
    action: ACCEPT
    reason: MVB12A is a metazoan fourth subunit of ESCRT-I and is directly supported by ESCRT-I composition and structural
      studies.
    additional_reference_ids: *id005
    supported_by: *id006
- term:
    id: GO:0010008
    label: endosome membrane
  evidence_type: NAS
  original_reference_id: PMID:32424346
  qualifier: located_in
  review:
    summary: endosome membrane localization is supported and relevant to MVB12A/ESCRT-I function.
    action: ACCEPT
    reason: MVB12A is an ESCRT-I subunit associated with endosomes/late-endosome membrane and endosomal cargo sorting.
    additional_reference_ids: *id009
    supported_by: *id010
- term:
    id: GO:0036258
    label: multivesicular body assembly
  evidence_type: NAS
  original_reference_id: PMID:32424346
  qualifier: involved_in
  review:
    summary: multivesicular body assembly is supported as part of MVB12A/ESCRT-I endosomal cargo sorting.
    action: ACCEPT
    reason: MVB12A/ESCRT-I supports ubiquitin-dependent endosomal cargo sorting, receptor down-regulation, and multivesicular
      body pathway transport.
    additional_reference_ids: *id001
    supported_by: *id002
- term:
    id: GO:0043328
    label: protein transport to vacuole involved in ubiquitin-dependent protein catabolic process via the multivesicular body
      sorting pathway
  evidence_type: NAS
  original_reference_id: PMID:32424346
  qualifier: involved_in
  review:
    summary: protein transport to vacuole involved in ubiquitin-dependent protein catabolic process via the multivesicular
      body sorting pathway is supported as part of MVB12A/ESCRT-I endosomal cargo sorting.
    action: ACCEPT
    reason: MVB12A/ESCRT-I supports ubiquitin-dependent endosomal cargo sorting, receptor down-regulation, and multivesicular
      body pathway transport.
    additional_reference_ids: *id001
    supported_by: *id002
- term:
    id: GO:0090148
    label: membrane fission
  evidence_type: NAS
  original_reference_id: PMID:32424346
  qualifier: involved_in
  review:
    summary: Membrane fission is supported as an ESCRT-I complex-level mechanism involving MVB12A-containing headpiece assemblies.
    action: ACCEPT
    reason: MVB12A is directly present in the structural ESCRT-I headpiece used to support ESCRT-I filament/scaffolding behavior,
      although the perturbation assay targeted VPS28.
    additional_reference_ids:
    - PMID:32424346
    - PMID:20588296
    - file:human/MVB12A/MVB12A-notes.md
    - file:human/MVB12A/MVB12A-deep-research-falcon.md
    supported_by:
    - &id023
      reference_id: PMID:32424346
      supporting_text: comprising TSG101-VPS28-VPS37B-MVB12A
    - &id024
      reference_id: PMID:32424346
      supporting_text: 22-amino acid fragment of MVB12A
    - &id025
      reference_id: PMID:32424346
      supporting_text: ESCRT-I is not merely a bridging adaptor
    - reference_id: file:human/MVB12A/MVB12A-deep-research-falcon.md
      supporting_text: MVB12A is not merely a passive adaptor but participates in active scaffolding for membrane remodeling
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18005716
  qualifier: enables
  review:
    summary: Protein binding from ESCRT-I reconstitution should be replaced by ESCRT-I complex membership.
    action: MODIFY
    reason: The interaction evidence supports complex membership rather than generic protein binding.
    proposed_replacement_terms:
    - id: GO:0000813
      label: ESCRT I complex
    additional_reference_ids: *id005
    supported_by: *id006
- term:
    id: GO:0046755
    label: viral budding
  evidence_type: IMP
  original_reference_id: PMID:18005716
  qualifier: involved_in
  review:
    summary: viral budding is directly supported but is a non-core host-pathogen context for this review.
    action: KEEP_AS_NON_CORE
    reason: MVB12A/MVB12 subunits regulate HIV/viral budding and maturation, but the core cellular proteostasis role is endosomal
      ESCRT-I cargo sorting.
    additional_reference_ids: *id003
    supported_by: *id004
- term:
    id: GO:0010008
    label: endosome membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-184269
  qualifier: located_in
  review:
    summary: endosome membrane localization is supported and relevant to MVB12A/ESCRT-I function.
    action: ACCEPT
    reason: MVB12A is an ESCRT-I subunit associated with endosomes/late-endosome membrane and endosomal cargo sorting.
    additional_reference_ids: *id009
    supported_by: *id010
- term:
    id: GO:0010008
    label: endosome membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3149434
  qualifier: located_in
  review:
    summary: endosome membrane localization is supported and relevant to MVB12A/ESCRT-I function.
    action: ACCEPT
    reason: MVB12A is an ESCRT-I subunit associated with endosomes/late-endosome membrane and endosomal cargo sorting.
    additional_reference_ids: *id009
    supported_by: *id010
- term:
    id: GO:0010008
    label: endosome membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3159232
  qualifier: located_in
  review:
    summary: endosome membrane localization is supported and relevant to MVB12A/ESCRT-I function.
    action: ACCEPT
    reason: MVB12A is an ESCRT-I subunit associated with endosomes/late-endosome membrane and endosomal cargo sorting.
    additional_reference_ids: *id009
    supported_by: *id010
- term:
    id: GO:0010008
    label: endosome membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-917696
  qualifier: located_in
  review:
    summary: endosome membrane localization is supported and relevant to MVB12A/ESCRT-I function.
    action: ACCEPT
    reason: MVB12A is an ESCRT-I subunit associated with endosomes/late-endosome membrane and endosomal cargo sorting.
    additional_reference_ids: *id009
    supported_by: *id010
- term:
    id: GO:0010008
    label: endosome membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-917730
  qualifier: located_in
  review:
    summary: endosome membrane localization is supported and relevant to MVB12A/ESCRT-I function.
    action: ACCEPT
    reason: MVB12A is an ESCRT-I subunit associated with endosomes/late-endosome membrane and endosomal cargo sorting.
    additional_reference_ids: *id009
    supported_by: *id010
- term:
    id: GO:0016236
    label: macroautophagy
  evidence_type: TAS
  original_reference_id: PMID:20588296
  qualifier: involved_in
  review:
    summary: Macroautophagy is over-annotated for MVB12A as written.
    action: MARK_AS_OVER_ANNOTATED
    reason: The broad ESCRT/autophagy review and VPS28-interface structural assay do not directly establish MVB12A as a core
      macroautophagy or phagophore-closure factor.
    proposed_replacement_terms:
    - id: GO:0000813
      label: ESCRT I complex
    - id: GO:0090148
      label: membrane fission
    additional_reference_ids:
    - PMID:20588296
    - PMID:31519728
    - PMID:32424346
    - file:human/MVB12A/MVB12A-notes.md
    supported_by:
    - reference_id: PMID:20588296
      supporting_text: viral budding, cytokinesis and, probably, autophagy
    - reference_id: PMID:20588296
      supporting_text: direct neck closure reaction in autophagy
    - reference_id: PMID:31519728
      supporting_text: identify the ESCRT-I subunit VPS37A as a critical component
    - reference_id: PMID:31519728
      supporting_text: required for autophagosome completion
    - reference_id: PMID:32424346
      supporting_text: Mutation of VPS28 helical interface residues blocks filament formation
- term:
    id: GO:0000813
    label: ESCRT I complex
  evidence_type: TAS
  original_reference_id: PMID:20588296
  qualifier: part_of
  review:
    summary: ESCRT-I complex membership is the central MVB12A cellular-component annotation.
    action: ACCEPT
    reason: MVB12A is a metazoan fourth subunit of ESCRT-I and is directly supported by ESCRT-I composition and structural
      studies.
    additional_reference_ids: *id005
    supported_by: *id006
- term:
    id: GO:0036258
    label: multivesicular body assembly
  evidence_type: TAS
  original_reference_id: PMID:20588296
  qualifier: involved_in
  review:
    summary: multivesicular body assembly is supported as part of MVB12A/ESCRT-I endosomal cargo sorting.
    action: ACCEPT
    reason: MVB12A/ESCRT-I supports ubiquitin-dependent endosomal cargo sorting, receptor down-regulation, and multivesicular
      body pathway transport.
    additional_reference_ids: *id001
    supported_by: *id002
- term:
    id: GO:0039702
    label: viral budding via host ESCRT complex
  evidence_type: TAS
  original_reference_id: PMID:20588296
  qualifier: involved_in
  review:
    summary: viral budding via host ESCRT complex is directly supported but is a non-core host-pathogen context for this review.
    action: KEEP_AS_NON_CORE
    reason: MVB12A/MVB12 subunits regulate HIV/viral budding and maturation, but the core cellular proteostasis role is endosomal
      ESCRT-I cargo sorting.
    additional_reference_ids: *id003
    supported_by: *id004
- term:
    id: GO:0019075
    label: virus maturation
  evidence_type: IMP
  original_reference_id: PMID:18005716
  qualifier: involved_in
  review:
    summary: virus maturation is directly supported but is a non-core host-pathogen context for this review.
    action: KEEP_AS_NON_CORE
    reason: MVB12A/MVB12 subunits regulate HIV/viral budding and maturation, but the core cellular proteostasis role is endosomal
      ESCRT-I cargo sorting.
    additional_reference_ids: *id003
    supported_by: *id004
- term:
    id: GO:0000813
    label: ESCRT I complex
  evidence_type: IDA
  original_reference_id: PMID:18005716
  qualifier: part_of
  review:
    summary: ESCRT-I complex membership is the central MVB12A cellular-component annotation.
    action: ACCEPT
    reason: MVB12A is a metazoan fourth subunit of ESCRT-I and is directly supported by ESCRT-I composition and structural
      studies.
    additional_reference_ids: *id005
    supported_by: *id006
- term:
    id: GO:0005813
    label: centrosome
  evidence_type: IDA
  original_reference_id: PMID:18005716
  qualifier: located_in
  review:
    summary: centrosome is supported as a localization/context row but is not the core MVB12A function.
    action: KEEP_AS_NON_CORE
    reason: The core proteostasis role is ESCRT-I endosomal cargo sorting; this localization is secondary or broad.
    additional_reference_ids: *id007
    supported_by: *id008
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:23533145
  qualifier: located_in
  review:
    summary: extracellular exosome is supported as a localization/context row but is not the core MVB12A function.
    action: KEEP_AS_NON_CORE
    reason: The core proteostasis role is ESCRT-I endosomal cargo sorting; this localization is secondary or broad.
    additional_reference_ids: *id007
    supported_by: *id008
- term:
    id: GO:0000813
    label: ESCRT I complex
  evidence_type: IDA
  original_reference_id: PMID:20654576
  qualifier: part_of
  review:
    summary: ESCRT-I complex membership is the central MVB12A cellular-component annotation.
    action: ACCEPT
    reason: MVB12A is a metazoan fourth subunit of ESCRT-I and is directly supported by ESCRT-I composition and structural
      studies.
    additional_reference_ids: *id005
    supported_by: *id006
- term:
    id: GO:0000813
    label: ESCRT I complex
  evidence_type: IDA
  original_reference_id: PMID:22232651
  qualifier: part_of
  review:
    summary: ESCRT-I complex membership is the central MVB12A cellular-component annotation.
    action: ACCEPT
    reason: MVB12A is a metazoan fourth subunit of ESCRT-I and is directly supported by ESCRT-I composition and structural
      studies.
    additional_reference_ids: *id005
    supported_by: *id006
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20654576
  qualifier: enables
  review:
    summary: Protein binding should be replaced by the more informative SH3 domain binding context.
    action: MODIFY
    reason: MVB12A/CFBP binds CD2AP/CIN85 SH3-domain proteins through a proline-rich motif regulated by Tyr204 phosphorylation.
    proposed_replacement_terms:
    - id: GO:0017124
      label: SH3 domain binding
    additional_reference_ids:
    - PMID:16895919
    - PMID:20654576
    - file:human/MVB12A/MVB12A-uniprot.txt
    - file:human/MVB12A/MVB12A-notes.md
    supported_by:
    - reference_id: PMID:16895919
      supporting_text: CIN85/CD2AP family was identified as a binding partner
    - reference_id: PMID:16895919
      supporting_text: recognized by one of the three Src-homology 3 domains
    - reference_id: PMID:20654576
      supporting_text: affects binding to CD2AP
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:20654576
  qualifier: located_in
  review:
    summary: cytosol is supported as a localization/context row but is not the core MVB12A function.
    action: KEEP_AS_NON_CORE
    reason: The core proteostasis role is ESCRT-I endosomal cargo sorting; this localization is secondary or broad.
    additional_reference_ids: *id007
    supported_by: *id008
- term:
    id: GO:0008289
    label: lipid binding
  evidence_type: IMP
  original_reference_id: PMID:22232651
  qualifier: enables
  review:
    summary: Lipid binding is correct but should be made more specific.
    action: MODIFY
    reason: MVB12A/MVB12B MABP domains bind acidic phospholipid-containing liposomes, so phospholipid binding is the more
      informative MF term.
    proposed_replacement_terms:
    - id: GO:0005543
      label: phospholipid binding
    additional_reference_ids:
    - PMID:22232651
    - file:human/MVB12A/MVB12A-notes.md
    - file:human/MVB12A/MVB12A-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:22232651
      supporting_text: MABP domains of the MVB12A and B subunits
    - reference_id: PMID:22232651
      supporting_text: bind in vitro to liposomes containing acidic lipids
    - reference_id: PMID:22232651
      supporting_text: coincidence detector for acidic phospholipids and protein ligands
    - reference_id: file:human/MVB12A/MVB12A-deep-research-falcon.md
      supporting_text: binds to acidic liposomes containing anionic lipids
- term:
    id: GO:0031982
    label: vesicle
  evidence_type: IDA
  original_reference_id: PMID:20654576
  qualifier: located_in
  review:
    summary: vesicle is supported as a localization/context row but is not the core MVB12A function.
    action: KEEP_AS_NON_CORE
    reason: The core proteostasis role is ESCRT-I endosomal cargo sorting; this localization is secondary or broad.
    additional_reference_ids: *id007
    supported_by: *id008
- term:
    id: GO:0042058
    label: regulation of epidermal growth factor receptor signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:20654576
  qualifier: involved_in
  review:
    summary: EGFR signaling regulation is supported as a substrate-specific MVB12A context.
    action: KEEP_AS_NON_CORE
    reason: MVB12A affects EGFR down-regulation through CD2AP/CIN85 and ESCRT-I, but EGFR signaling is a cargo/context-specific
      consequence rather than the core function.
    additional_reference_ids: *id013
    supported_by: *id014
- term:
    id: GO:0043130
    label: ubiquitin binding
  evidence_type: IMP
  original_reference_id: PMID:20654576
  qualifier: enables
  review:
    summary: Ubiquitin binding is plausible from the GOA/UniProt row but cannot be confirmed from the cached abstract.
    action: UNDECIDED
    reason: The row cites PMID:20654576, but the cached abstract available locally does not expose the underlying ubiquitin-binding
      experiment. Verify full text before accepting or replacing this MF annotation.
    additional_reference_ids:
    - PMID:20654576
    - file:human/MVB12A/MVB12A-notes.md
    supported_by:
    - reference_id: file:human/MVB12A/MVB12A-notes.md
      supporting_text: that row should remain undecided pending full-text confirmation
- term:
    id: GO:0043162
    label: ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway
  evidence_type: IC
  original_reference_id: PMID:20654576
  qualifier: involved_in
  review:
    summary: ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway is supported as part
      of MVB12A/ESCRT-I endosomal cargo sorting.
    action: ACCEPT
    reason: MVB12A/ESCRT-I supports ubiquitin-dependent endosomal cargo sorting, receptor down-regulation, and multivesicular
      body pathway transport.
    additional_reference_ids: *id001
    supported_by: *id002
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  qualifier: located_in
  review:
    summary: extracellular exosome is supported as a localization/context row but is not the core MVB12A function.
    action: KEEP_AS_NON_CORE
    reason: The core proteostasis role is ESCRT-I endosomal cargo sorting; this localization is secondary or broad.
    additional_reference_ids: *id007
    supported_by: *id008
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative
    changes to GO terms applied by UniProt
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:18005716
  title: Identification of human MVB12 proteins as ESCRT-I subunits that function in HIV budding.
  findings: []
- id: PMID:19056867
  title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
  findings: []
- id: PMID:20588296
  title: 'Membrane budding and scission by the ESCRT machinery: it''s all in the neck.'
  findings: []
- id: PMID:20654576
  title: Distinct functions of human MVB12A and MVB12B in the ESCRT-I dependent on their posttranslational modifications.
  findings: []
- id: PMID:22232651
  title: "Structural basis for membrane targeting by the MVB12-associated \u03B2-prism domain of the human ESCRT-I MVB12 subunit."
  findings: []
- id: PMID:23533145
  title: In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine.
  findings: []
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease networks.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:32424346
  title: A helical assembly of human ESCRT-I scaffolds reverse-topology membrane scission.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
- id: Reactome:R-HSA-184269
  title: Monoubiquitinated N-myristoyl GAG polyprotein is targeted to the late endosomal vesicle membrane by the ESCRT-I complex
  findings: []
- id: Reactome:R-HSA-3149434
  title: Transport of GAG to the Plasma Membrane
  findings: []
- id: Reactome:R-HSA-3159232
  title: Recruitment Of HIV Virion Budding Machinery
  findings: []
- id: Reactome:R-HSA-917696
  title: Cargo Sequestration
  findings: []
- id: Reactome:R-HSA-917730
  title: Cargo Recognition And Sorting
  findings: []
- id: PMID:16895919
  title: CFBP is a novel tyrosine-phosphorylated protein that might function as a regulator of CIN85/CD2AP.
  findings: []
- id: PMID:31519728
  title: VPS37A directs ESCRT recruitment for phagophore closure.
  findings: []
- id: file:human/MVB12A/MVB12A-uniprot.txt
  title: UniProtKB record for human MVB12A
  findings: []
- id: file:human/MVB12A/MVB12A-notes.md
  title: MVB12A review notes
  findings: []
- id: file:human/MVB12A/MVB12A-deep-research-falcon.md
  title: Falcon deep research report for MVB12A
  findings: []
  reference_review:
    relevance: HIGH
    correctness: UNVERIFIED
    review_notes: >-
      LLM-synthesized deep research report (Edison/Falcon). Useful as a structured synthesis
      that is consistent with the primary literature already cited in this review (Morita 2007,
      Audhya 2007, Boura/Hurley 2012, Flower 2020). It correctly anchors MVB12A as a
      structural/adapter fourth subunit of ESCRT-I (UMA domain) with an N-terminal MABP
      membrane-targeting domain, and it adds one genuinely new MVB12A-specific finding: the 2025
      Zhang et al. study (mBio, doi:10.1128/mbio.00979-25) showing MVB12A knockdown impairs
      beta-coronavirus virion egress without blocking assembly. CAUTION: many statements in the
      report ascribe whole-ESCRT-I-complex or pan-MVB12-family functions (cytokinesis/abscission,
      membrane repair, autophagosome closure, exosome biogenesis, ubiquitin-dependent MVB sorting)
      to MVB12A by inference from the holo-complex or from the MVB12B/UBAP1 paralogs rather than
      from MVB12A-specific perturbation; e.g. UBAP1-, not MVB12A-, containing ESCRT-I is the one
      shown to be required for ubiquitin-dependent MVB sorting (Stefani 2011), and the
      autophagosome-closure assay perturbed VPS28, not MVB12A (Flower 2020). MVB12A-specific
      claims are kept anchored; holo-complex/paralog inferences are not used to upgrade
      annotations. Identifier and supporting-text claims have not been independently verified
      against the cited primary papers, hence UNVERIFIED.
core_functions:
- description: MVB12A is a fourth subunit of metazoan ESCRT-I complexes and helps organize MVB12A-containing TSG101-VPS28-VPS37
    ESCRT-I assemblies.
  directly_involved_in:
  - id: GO:0036258
    label: multivesicular body assembly
  - id: GO:0090148
    label: membrane fission
  locations:
  - id: GO:0010008
    label: endosome membrane
  - id: GO:0031902
    label: late endosome membrane
  in_complex:
    id: GO:0000813
    label: ESCRT I complex
  supported_by:
  - *id015
  - *id016
  - *id017
  - *id018
  - *id019
  - *id020
  - *id021
  - *id022
  - *id023
  - *id024
  - *id025
  - *id026
  - *id027
  - *id028
- description: MVB12A supports endosomal sorting and down-regulation of ubiquitinated receptor cargo, including EGFR pathway
    cargo context.
  molecular_function:
    id: GO:0005543
    label: phospholipid binding
  directly_involved_in:
  - id: GO:0032510
    label: endosome to lysosome transport via multivesicular body sorting pathway
  - id: GO:0043162
    label: ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway
  - id: GO:0032801
    label: receptor catabolic process
  locations:
  - id: GO:0005768
    label: endosome
  - id: GO:0010008
    label: endosome membrane
  in_complex:
    id: GO:0000813
    label: ESCRT I complex
  supported_by:
  - *id029
  - *id030
  - *id031
  - *id032
  - *id033
  - *id034
  - *id035
  - *id036
  - *id037
  - *id038
proposed_new_terms: []
suggested_questions:
- question: Should MVB12A macroautophagy annotations be retired, modified to ESCRT-I membrane fission, or kept non-core pending
    MVB12A-specific phagophore-closure perturbation evidence?
  experts:
  - GO autophagy editors
  - GO ESCRT curators
- question: Should MVB12A generic protein-binding annotations be replaced by ESCRT-I complex membership, SH3 domain binding,
    phospholipid binding, and ubiquitin binding where the evidence supports those more specific terms?
  experts:
  - GO molecular function editors
  - UniProt curators
suggested_experiments:
- experiment_type: MVB12A-specific phagophore closure assay
  hypothesis: MVB12A-containing ESCRT-I assemblies contribute to ESCRT-I scaffold mechanics, but MVB12A-specific loss has
    not been shown to be required for phagophore closure.
  description: Use MVB12A knockout/rescue in HT-LC3 autophagosome closure assays, with VPS37A and VPS28 helical-interface
    perturbations as controls, and compare effects on EGFR MVB sorting.
- experiment_type: MVB12A molecular-function refinement
  hypothesis: MVB12A membrane and cargo recognition is better represented by phospholipid binding, ubiquitin binding, and
    SH3-domain-binding contexts than generic protein binding.
  description: Test purified MVB12A domains for acidic phospholipid binding, ubiquitin binding, and CD2AP/CIN85 SH3-domain
    binding using matched mutants and rescue readouts in EGFR down-regulation assays.

MVB12A

Gene Description

Existing Annotations Review

Core Functions

MVB12A is a fourth subunit of metazoan ESCRT-I complexes and helps organize MVB12A-containing TSG101-VPS28-VPS37 ESCRT-I assemblies.

MVB12A supports endosomal sorting and down-regulation of ubiquitinated receptor cargo, including EGFR pathway cargo context.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Comprehensive Research Report: MVB12A (FAM125A) - Gene Function, Localization, and Biological Pathways

Gene Identity and Overview

Primary Function and Molecular Activity

Structural Adapter Role

Complex Stoichiometry and Assembly

Protein Domains and Molecular Interactions

UMA Domain: ESCRT-I Integration Module

Binding Selectivity: TSG101-VPS37 Binary Complex Recognition

MABP Domain: Membrane Targeting Module

Subcellular Localization

Biological Pathways and Cellular Processes

1. Multivesicular Body (MVB) Biogenesis and Endosomal Sorting

2. Viral Budding and Egress

3. Autophagosome Closure

4. Cytokinesis and Cell Division

5. Membrane Repair and Organelle Homeostasis

6. Exosome and Extracellular Vesicle Formation

Structural Insights and Higher-Order Assembly

Summary of Protein Interactions and Structural Features

Evolutionary and Comparative Perspectives

Recent Developments (2023-2025)

Conclusions

Artifacts

Citations

📚 Additional Documentation

Notes

MVB12A review notes

Scope

Evidence synthesis

Falcon

Description cleanup note

Pn Notes

MVB12A PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

PN row 1: Autophagy-Lysosome Pathway | Autophagosome closure maturation and lysosome fusion | Sealing of autophagophore membrane | ESCRT-I complex component

PN row 2: Ubiquitin Proteasome System | Ubiquitin and UBL binding | trafficking | ESCRT-I complex | idiosyncratic Ub binding / other

Projected GO annotations (2)

Note

📄 View Raw YAML