Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0043162 ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway	IBA GO_REF:0000033	ACCEPT	Summary: ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway is supported as part of the core VPS37D/ESCRT-I endosomal cargo-sorting role. Reason: VPS37D is annotated as an ESCRT-I subunit required for ubiquitin-dependent endosomal cargo sorting into multivesicular bodies. Supporting Evidence: file:human/VPS37D/VPS37D-uniprot.txt Required for the sorting of endocytic file:human/VPS37D/VPS37D-uniprot.txt ubiquitinated cargos into multivesicular bodies PMID:15218037 sorting ubiquitylated protein cargoes into multivesicular bodies PMID:18005716 plays essential roles in HIV budding and endosomal protein sorting
GO:0000813 ESCRT I complex	IBA GO_REF:0000033	ACCEPT	Summary: ESCRT-I complex membership is the central VPS37D cellular-component annotation. Reason: VPS37D is a VPS37-family ESCRT-I subunit in TSG101-VPS28-VPS37-MVB12/UBAP variant complexes, although direct VPS37D-specific functional evidence is limited. The falcon deep research independently corroborates VPS37D as a bona fide core ESCRT-I subunit while cautioning that it is the least functionally characterized of the four human paralogs. Supporting Evidence: file:human/VPS37D/VPS37D-uniprot.txt Component of the ESCRT-I complex file:human/VPS37D/VPS37D-uniprot.txt which consists of TSG101, VPS28, a VPS37 file:human/VPS37D/VPS37D-uniprot.txt Interacts with TSG101 and MVB12A PMID:15218037 proteins (VPS37A-D) that share weak but significant sequence similarity PMID:18005716 All ESCRT-I complexes contain three common subunits (TSG101, VPS28, and VPS37) PMID:22405001 complex with Vps23/TSG101, VPS28, and VPS37 file:human/VPS37D/VPS37D-deep-research-falcon.md confirmed bona fide human ESCRT-I core subunit; included among mammalian VPS37A-D paralogs file:human/VPS37D/VPS37D-deep-research-falcon.md Least functionally characterized of the four human paralogs in primary mechanistic literature
GO:0006612 protein targeting to membrane	IBA GO_REF:0000033	MODIFY	Summary: protein targeting to membrane is too broad for VPS37D ESCRT-I function. Reason: The supported process is ESCRT-I-dependent endosomal cargo sorting into the MVB pathway, not generic protein targeting. Proposed replacements: ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway multivesicular body assembly Supporting Evidence: file:human/VPS37D/VPS37D-uniprot.txt Required for the sorting of endocytic file:human/VPS37D/VPS37D-uniprot.txt ubiquitinated cargos into multivesicular bodies PMID:15218037 sorting ubiquitylated protein cargoes into multivesicular bodies PMID:18005716 plays essential roles in HIV budding and endosomal protein sorting
GO:0006623 protein targeting to vacuole	IBA GO_REF:0000033	MODIFY	Summary: protein targeting to vacuole is too broad for VPS37D ESCRT-I function. Reason: The supported process is ESCRT-I-dependent endosomal cargo sorting into the MVB pathway, not generic protein targeting. Proposed replacements: ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway multivesicular body assembly Supporting Evidence: file:human/VPS37D/VPS37D-uniprot.txt Required for the sorting of endocytic file:human/VPS37D/VPS37D-uniprot.txt ubiquitinated cargos into multivesicular bodies PMID:15218037 sorting ubiquitylated protein cargoes into multivesicular bodies PMID:18005716 plays essential roles in HIV budding and endosomal protein sorting
GO:0000813 ESCRT I complex	IEA GO_REF:0000117	ACCEPT	Summary: ESCRT-I complex membership is the central VPS37D cellular-component annotation. Reason: VPS37D is a VPS37-family ESCRT-I subunit in TSG101-VPS28-VPS37-MVB12/UBAP variant complexes, although direct VPS37D-specific functional evidence is limited. Supporting Evidence: file:human/VPS37D/VPS37D-uniprot.txt Component of the ESCRT-I complex file:human/VPS37D/VPS37D-uniprot.txt which consists of TSG101, VPS28, a VPS37 file:human/VPS37D/VPS37D-uniprot.txt Interacts with TSG101 and MVB12A PMID:15218037 proteins (VPS37A-D) that share weak but significant sequence similarity PMID:18005716 All ESCRT-I complexes contain three common subunits (TSG101, VPS28, and VPS37) PMID:22405001 complex with Vps23/TSG101, VPS28, and VPS37 file:human/VPS37D/VPS37D-deep-research-falcon.md confirmed bona fide human ESCRT-I core subunit; included among mammalian VPS37A-D paralogs file:human/VPS37D/VPS37D-deep-research-falcon.md Least functionally characterized of the four human paralogs in primary mechanistic literature
GO:0031902 late endosome membrane	IEA GO_REF:0000044	ACCEPT	Summary: late endosome membrane localization is supported and relevant to VPS37D/ESCRT-I function. Reason: VPS37D is a peripheral late-endosome/endosome-membrane ESCRT-I component in local and Reactome context. Supporting Evidence: file:human/VPS37D/VPS37D-uniprot.txt Late endosome membrane file:human/VPS37D/VPS37D-uniprot.txt Peripheral membrane protein
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 VPS37D function. Reason: The informative annotations are ESCRT-I complex membership and endosomal MVB sorting, not generic protein binding from a broad interaction screen. The falcon deep research notes that, unlike VPS37B/C, VPS37D does not have the selective SH3YL1 or CDIP1 interactions reported for those paralogs, so no specific informative interaction partner can be assigned to VPS37D from the literature to replace this generic term. Proposed replacements: ESCRT I complex Supporting Evidence: file:human/VPS37D/VPS37D-notes.md The generic `protein binding` row comes from a broad interactome annotation file:human/VPS37D/VPS37D-deep-research-falcon.md does not show the same highlighted SH3YL1 or CDIP1 preference reported for VPS37B/C
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 VPS37D cellular-component annotation. Reason: VPS37D is a VPS37-family ESCRT-I subunit in TSG101-VPS28-VPS37-MVB12/UBAP variant complexes, although direct VPS37D-specific functional evidence is limited. Supporting Evidence: file:human/VPS37D/VPS37D-uniprot.txt Component of the ESCRT-I complex file:human/VPS37D/VPS37D-uniprot.txt which consists of TSG101, VPS28, a VPS37 file:human/VPS37D/VPS37D-uniprot.txt Interacts with TSG101 and MVB12A PMID:15218037 proteins (VPS37A-D) that share weak but significant sequence similarity PMID:18005716 All ESCRT-I complexes contain three common subunits (TSG101, VPS28, and VPS37) PMID:22405001 complex with Vps23/TSG101, VPS28, and VPS37 file:human/VPS37D/VPS37D-deep-research-falcon.md confirmed bona fide human ESCRT-I core subunit; included among mammalian VPS37A-D paralogs file:human/VPS37D/VPS37D-deep-research-falcon.md Least functionally characterized of the four human paralogs in primary mechanistic literature
GO:0000813 ESCRT I complex	IPI PMID:21757351 UBAP1 is a component of an endosome-specific ESCRT-I complex...	ACCEPT	Summary: ESCRT-I complex membership is correct for VPS37D, but PMID:21757351 is indirect for this isoform. Reason: The term is correct from UniProt and shared ESCRT-I evidence; PMID:21757351 mainly defines an endosome-specific UBAP1/VPS37A complex and should not be treated as direct VPS37D functional support. Supporting Evidence: file:human/VPS37D/VPS37D-uniprot.txt Component of the ESCRT-I complex file:human/VPS37D/VPS37D-uniprot.txt which consists of TSG101, VPS28, a VPS37 file:human/VPS37D/VPS37D-uniprot.txt Interacts with TSG101 and MVB12A PMID:15218037 proteins (VPS37A-D) that share weak but significant sequence similarity PMID:18005716 All ESCRT-I complexes contain three common subunits (TSG101, VPS28, and VPS37) PMID:21757351 contains VPS37A but not VPS37C
GO:0010008 endosome membrane	NAS PMID:32424346 A helical assembly of human ESCRT-I scaffolds reverse-topolo...	ACCEPT	Summary: endosome membrane is correct for VPS37D, but PMID:32424346 is indirect for this isoform. Reason: Endosome-membrane localization is supported by VPS37D context; PMID:32424346 supports general ESCRT-I mechanism using a VPS37B-containing headpiece. Supporting Evidence: file:human/VPS37D/VPS37D-uniprot.txt Late endosome membrane file:human/VPS37D/VPS37D-uniprot.txt Peripheral membrane protein PMID:32424346 comprising TSG101-VPS28-VPS37B-MVB12A
GO:0036258 multivesicular body assembly	NAS PMID:32424346 A helical assembly of human ESCRT-I scaffolds reverse-topolo...	ACCEPT	Summary: multivesicular body assembly is biologically consistent with VPS37D ESCRT-I function, but PMID:32424346 is indirect for this isoform. Reason: The term is supported by VPS37D ESCRT-I/MVB context; PMID:32424346 supports general ESCRT-I mechanism using a VPS37B-containing headpiece. Supporting Evidence: file:human/VPS37D/VPS37D-uniprot.txt Required for the sorting of endocytic file:human/VPS37D/VPS37D-uniprot.txt ubiquitinated cargos into multivesicular bodies PMID:15218037 sorting ubiquitylated protein cargoes into multivesicular bodies PMID:18005716 plays essential roles in HIV budding and endosomal protein sorting PMID:32424346 comprising TSG101-VPS28-VPS37B-MVB12A
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 biologically consistent with VPS37D ESCRT-I function, but PMID:32424346 is indirect for this isoform. Reason: The term is supported by VPS37D ESCRT-I/MVB context; PMID:32424346 supports general ESCRT-I mechanism using a VPS37B-containing headpiece. Supporting Evidence: file:human/VPS37D/VPS37D-uniprot.txt Required for the sorting of endocytic file:human/VPS37D/VPS37D-uniprot.txt ubiquitinated cargos into multivesicular bodies PMID:15218037 sorting ubiquitylated protein cargoes into multivesicular bodies PMID:18005716 plays essential roles in HIV budding and endosomal protein sorting PMID:32424346 comprising TSG101-VPS28-VPS37B-MVB12A
GO:0090148 membrane fission	NAS PMID:32424346 A helical assembly of human ESCRT-I scaffolds reverse-topolo...	MARK AS OVER ANNOTATED	Summary: Membrane fission is a broad ESCRT-I mechanism annotation and is over-transferred for VPS37D as written. Reason: The cited structural/autophagy work directly tested a VPS37B-containing headpiece and VPS28 interface mutants, not VPS37D; the safer VPS37D annotations are ESCRT-I complex and MVB sorting. Proposed replacements: ESCRT I complex multivesicular body assembly Supporting Evidence: PMID:32424346 comprising TSG101-VPS28-VPS37B-MVB12A PMID:32424346 ESCRT-I is not merely a bridging adaptor
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 VPS37D. Reason: The accessible ESCRT autophagy evidence is broad or VPS37A-specific; there is not enough direct evidence to make VPS37D a phagophore-closure/autophagosome assembly factor. The autophagy-specialized ESCRT-I module is built on VPS37A's N-terminal ubiquitin E2 variant-like (UEVL) region; the falcon deep research notes that no equivalent VPS37A-like autophagy UEVL specialization has been established for VPS37D, reinforcing that macroautophagy should not be a VPS37D core annotation. Proposed replacements: ESCRT I complex 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 file:human/VPS37D/VPS37D-deep-research-falcon.md no VPS37A-like autophagy UEVL specialization has been established in the cited studies
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 VPS37D cellular-component annotation. Reason: VPS37D is a VPS37-family ESCRT-I subunit in TSG101-VPS28-VPS37-MVB12/UBAP variant complexes, although direct VPS37D-specific functional evidence is limited. Supporting Evidence: file:human/VPS37D/VPS37D-uniprot.txt Component of the ESCRT-I complex file:human/VPS37D/VPS37D-uniprot.txt which consists of TSG101, VPS28, a VPS37 file:human/VPS37D/VPS37D-uniprot.txt Interacts with TSG101 and MVB12A PMID:15218037 proteins (VPS37A-D) that share weak but significant sequence similarity PMID:18005716 All ESCRT-I complexes contain three common subunits (TSG101, VPS28, and VPS37) PMID:22405001 complex with Vps23/TSG101, VPS28, and VPS37 file:human/VPS37D/VPS37D-deep-research-falcon.md confirmed bona fide human ESCRT-I core subunit; included among mammalian VPS37A-D paralogs file:human/VPS37D/VPS37D-deep-research-falcon.md Least functionally characterized of the four human paralogs in primary mechanistic literature
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 the core VPS37D/ESCRT-I endosomal cargo-sorting role. Reason: VPS37D is annotated as an ESCRT-I subunit required for ubiquitin-dependent endosomal cargo sorting into multivesicular bodies. Supporting Evidence: file:human/VPS37D/VPS37D-uniprot.txt Required for the sorting of endocytic file:human/VPS37D/VPS37D-uniprot.txt ubiquitinated cargos into multivesicular bodies PMID:15218037 sorting ubiquitylated protein cargoes into multivesicular bodies PMID:18005716 plays essential roles in HIV budding and endosomal protein sorting
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 a supported ESCRT context but is not the core VPS37D proteostasis function. Reason: Viral budding uses ESCRT-I machinery, but VPS37D-specific direct viral-budding evidence is limited and the core cellular role remains endosomal ESCRT-I cargo sorting. Supporting Evidence: PMID:18005716 plays essential roles in HIV budding and endosomal protein sorting PMID:20588296 viral budding, cytokinesis and, probably, autophagy
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 VPS37D cellular-component annotation. Reason: VPS37D is a VPS37-family ESCRT-I subunit in TSG101-VPS28-VPS37-MVB12/UBAP variant complexes, although direct VPS37D-specific functional evidence is limited. Supporting Evidence: file:human/VPS37D/VPS37D-uniprot.txt Component of the ESCRT-I complex file:human/VPS37D/VPS37D-uniprot.txt which consists of TSG101, VPS28, a VPS37 file:human/VPS37D/VPS37D-uniprot.txt Interacts with TSG101 and MVB12A PMID:15218037 proteins (VPS37A-D) that share weak but significant sequence similarity PMID:18005716 All ESCRT-I complexes contain three common subunits (TSG101, VPS28, and VPS37) PMID:22405001 complex with Vps23/TSG101, VPS28, and VPS37 file:human/VPS37D/VPS37D-deep-research-falcon.md confirmed bona fide human ESCRT-I core subunit; included among mammalian VPS37A-D paralogs file:human/VPS37D/VPS37D-deep-research-falcon.md Least functionally characterized of the four human paralogs in primary mechanistic literature
GO:0070062 extracellular exosome	HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres...	KEEP AS NON CORE	Summary: Extracellular exosome is a high-throughput proteomics/localization context and not a core VPS37D annotation. Reason: Exosome detection is not the central VPS37D ESCRT-I endosomal sorting function. Supporting Evidence: PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exosomes PMID:23533145 In-depth proteomic analyses of exosomes
GO:0070062 extracellular exosome	HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos...	KEEP AS NON CORE	Summary: Extracellular exosome is a high-throughput proteomics/localization context and not a core VPS37D annotation. Reason: Exosome detection is not the central VPS37D ESCRT-I endosomal sorting function. Supporting Evidence: 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:22405001 The UBAP1 subunit of ESCRT-I interacts with ubiquitin via a ...	ACCEPT	Summary: ESCRT-I complex membership is the central VPS37D cellular-component annotation. Reason: VPS37D is a VPS37-family ESCRT-I subunit in TSG101-VPS28-VPS37-MVB12/UBAP variant complexes, although direct VPS37D-specific functional evidence is limited. Supporting Evidence: file:human/VPS37D/VPS37D-uniprot.txt Component of the ESCRT-I complex file:human/VPS37D/VPS37D-uniprot.txt which consists of TSG101, VPS28, a VPS37 file:human/VPS37D/VPS37D-uniprot.txt Interacts with TSG101 and MVB12A PMID:15218037 proteins (VPS37A-D) that share weak but significant sequence similarity PMID:18005716 All ESCRT-I complexes contain three common subunits (TSG101, VPS28, and VPS37) PMID:22405001 complex with Vps23/TSG101, VPS28, and VPS37 file:human/VPS37D/VPS37D-deep-research-falcon.md confirmed bona fide human ESCRT-I core subunit; included among mammalian VPS37A-D paralogs file:human/VPS37D/VPS37D-deep-research-falcon.md Least functionally characterized of the four human paralogs in primary mechanistic literature
GO:0010008 endosome membrane	TAS Reactome:R-HSA-184269	ACCEPT	Summary: endosome membrane localization is supported and relevant to VPS37D/ESCRT-I function. Reason: VPS37D is a peripheral late-endosome/endosome-membrane ESCRT-I component in local and Reactome context. Supporting Evidence: file:human/VPS37D/VPS37D-uniprot.txt Late endosome membrane file:human/VPS37D/VPS37D-uniprot.txt Peripheral membrane protein
GO:0010008 endosome membrane	TAS Reactome:R-HSA-3149434	ACCEPT	Summary: endosome membrane localization is supported and relevant to VPS37D/ESCRT-I function. Reason: VPS37D is a peripheral late-endosome/endosome-membrane ESCRT-I component in local and Reactome context. Supporting Evidence: file:human/VPS37D/VPS37D-uniprot.txt Late endosome membrane file:human/VPS37D/VPS37D-uniprot.txt Peripheral membrane protein
GO:0010008 endosome membrane	TAS Reactome:R-HSA-3159232	ACCEPT	Summary: endosome membrane localization is supported and relevant to VPS37D/ESCRT-I function. Reason: VPS37D is a peripheral late-endosome/endosome-membrane ESCRT-I component in local and Reactome context. Supporting Evidence: file:human/VPS37D/VPS37D-uniprot.txt Late endosome membrane file:human/VPS37D/VPS37D-uniprot.txt Peripheral membrane protein
GO:0010008 endosome membrane	TAS Reactome:R-HSA-917696	ACCEPT	Summary: endosome membrane localization is supported and relevant to VPS37D/ESCRT-I function. Reason: VPS37D is a peripheral late-endosome/endosome-membrane ESCRT-I component in local and Reactome context. Supporting Evidence: file:human/VPS37D/VPS37D-uniprot.txt Late endosome membrane file:human/VPS37D/VPS37D-uniprot.txt Peripheral membrane protein
GO:0010008 endosome membrane	TAS Reactome:R-HSA-917730	ACCEPT	Summary: endosome membrane localization is supported and relevant to VPS37D/ESCRT-I function. Reason: VPS37D is a peripheral late-endosome/endosome-membrane ESCRT-I component in local and Reactome context. Supporting Evidence: file:human/VPS37D/VPS37D-uniprot.txt Late endosome membrane file:human/VPS37D/VPS37D-uniprot.txt Peripheral membrane protein

Core Functions

VPS37D is a VPS37-family ESCRT-I subunit that supports ESCRT-I complex organization and ubiquitin-dependent endosomal cargo sorting into multivesicular bodies.

Directly Involved In:

ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway multivesicular body assembly

Cellular Locations:

endosome membrane late endosome membrane

In Complex:

ESCRT I complex

Supporting Evidence:

file:human/VPS37D/VPS37D-uniprot.txt
Component of the ESCRT-I complex
file:human/VPS37D/VPS37D-uniprot.txt
which consists of TSG101, VPS28, a VPS37
file:human/VPS37D/VPS37D-uniprot.txt
Interacts with TSG101 and MVB12A
PMID:15218037
proteins (VPS37A-D) that share weak but significant sequence similarity
PMID:18005716
All ESCRT-I complexes contain three common subunits (TSG101, VPS28, and VPS37)
PMID:22405001
complex with Vps23/TSG101, VPS28, and VPS37
file:human/VPS37D/VPS37D-uniprot.txt
Required for the sorting of endocytic
file:human/VPS37D/VPS37D-uniprot.txt
ubiquitinated cargos into multivesicular bodies
PMID:15218037
sorting ubiquitylated protein cargoes into multivesicular bodies
PMID:18005716
plays essential roles in HIV budding and endosomal protein sorting
file:human/VPS37D/VPS37D-uniprot.txt
Late endosome membrane
file:human/VPS37D/VPS37D-uniprot.txt
Peripheral membrane protein

References

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:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

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:21757351

UBAP1 is a component of an endosome-specific ESCRT-I complex that is essential for MVB sorting.

PMID:22405001

The UBAP1 subunit of ESCRT-I interacts with ubiquitin via a SOUBA domain.

PMID:23533145

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

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.

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:15218037

The human endosomal sorting complex required for transport (ESCRT-I) and its role in HIV-1 budding.

PMID:31519728

VPS37A directs ESCRT recruitment for phagophore closure.

file:human/VPS37D/VPS37D-uniprot.txt

UniProtKB record for human VPS37D

file:human/VPS37D/VPS37D-notes.md

VPS37D review notes

file:human/VPS37D/VPS37D-deep-research-falcon.md

Falcon deep research report for VPS37D

Suggested Experiments

Experiment: Compare VPS37A, VPS37B, VPS37C, and VPS37D depletion/rescue in HT-LC3 autophagosome closure assays and parallel EGFR or tetherin MVB-sorting assays, using endogenous expression or matched rescue levels.

Hypothesis: VPS37A, but not necessarily VPS37D, is the VPS37 paralog specialized for phagophore closure.

Type: VPS37 paralog phagophore closure comparison

Experiment: Use VPS37D-specific knockout-rescue with quantitative cargo degradation and ESCRT recruitment readouts, controlling for VPS37A/B/C compensation.

Hypothesis: VPS37D participates in a subset of ESCRT-I cargo-sorting contexts but lacks direct evidence for autophagosome closure.

Type: VPS37D-specific ESCRT-I cargo-sorting assay

Deep Research

Falcon

(VPS37D-deep-research-falcon.md)

Comprehensive Research Report: VPS37D (UniProt: Q86XT2), Human ESCRT-I Component Falcon Edison Scientific Literature 35 citations 2 artifacts 2026-06-20T06:27:23.195023

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: VPS37D (UniProt: Q86XT2), Human ESCRT-I Component

1. Gene and Protein Identity Verification

VPS37D is unambiguously defined as a human gene encoding the vacuolar protein sorting-associated protein 37D (VPS37D), part of the ESCRT-I complex. It is also referenced as WBSCR24, and its UniProt/Swiss-Prot accession is Q86XT2. Literature consistently refers to human VPS37D as a paralog within the VPS37 protein family, showing the requisite Mod(r) domain and fitting the domain structure and family criteria listed in UniProt. No ambiguity with alternate genes or non-human proteins was found (torre2024preservinggenomeintegrity pages 1-3, hurley2025theexpandingrepertoire pages 2-3, flower2020ahelicalassembly pages 1-2).

2. Key Concepts, Definitions, and Current Understanding

VPS37D is one of four VPS37 paralogs (A, B, C, D) that serve as core structural components of the heterotetrameric ESCRT-I complex: TSG101, VPS28, one VPS37 family member, and a MVB12-like subunit (either MVB12A/B, UBAP1, UBA1L, or UMAD1). This complex is central for reverse-topology membrane scission during cargo trafficking to lysosomes, autophagosome closure, cytokinetic abscission, nuclear envelope repair, and more (vietri2020themanyfunctions pages 1-2, hurley2025theexpandingrepertoire pages 1-2, flower2020ahelicalassembly pages 1-2).

VPS37 paralogs contribute structural and possibly pathway-specific diversity to ESCRT-I complexes (glover2023umad1contributesto pages 1-3, hasegawa2019sh3yl1cooperateswith pages 1-2, inukai2021thenovelalg2 pages 1-2). While VPS37A is uniquely specialized for autophagic membrane closure, VPS37D's precise functional specialization remains less detailed, but it is verified as a core ESCRT-I structural subunit.

VPS37 paralog	Key domains / motifs	Unique features distinguishing each paralog	Known interacting partners in ESCRT-I complex	Specific cellular functions with strongest evidence	Disease associations / translational relevance
VPS37A	Conserved Mod(r) domain shared across VPS37 family; distinctive N-terminal ubiquitin E2 variant-like (UEVL) region required for autophagosome closure but dispensable for core ESCRT-I assembly and EGFR endosomal sorting (hamamoto2024unveilingthephysiological pages 3-5, takahashi2019vps37adirectsescrt pages 1-2)	Best-characterized VPS37 paralog; uniquely directs ESCRT recruitment to phagophores through its N-terminus; forms a specialized autophagy-relevant ESCRT-I module not shared by all paralogs (hamamoto2024unveilingthephysiological pages 3-5, takahashi2019vps37adirectsescrt pages 1-2)	Core ESCRT-I partners TSG101 and VPS28; can assemble with UBAP1 in an endosome/autophagy-adapted ESCRT-I complex; recruits downstream CHMP2A and VPS4-dependent closure machinery during autophagy (hamamoto2024unveilingthephysiological pages 3-5, takahashi2019vps37adirectsescrt pages 1-2, flower2020ahelicalassembly pages 1-2)	Endosomal sorting as an ESCRT-I core subunit; especially important in autophagosome/phagophore closure by directing ESCRT machinery to LC3-positive phagophores; contributes to broader reverse-topology membrane scission pathways (hamamoto2024unveilingthephysiological pages 1-3, hamamoto2024unveilingthephysiological pages 3-5, takahashi2019vps37adirectsescrt pages 1-2, vietri2020themanyfunctions pages 1-2)	Frequently lost/downregulated in solid tumors; associated with hepatocellular carcinoma history and worse survival when deleted; depletion linked to hyperglycemia/insulin resistance in review literature; reduced with VPS37B in colorectal cancer cohorts (hamamoto2024unveilingthephysiological pages 3-5, hurley2025theexpandingrepertoire pages 2-3, kolmus2021concurrentdepletionof pages 4-7)
VPS37B	Conserved Mod(r) domain; contains two PxLPxR motifs noted in comparison with VPS37C/D; has a proline-rich region architecture distinct from some other paralogs (hasegawa2019sh3yl1cooperateswith pages 1-2, inukai2021thenovelalg2 pages 1-2)	Strong evidence for selective paralog-specific interactions; binds SH3YL1 in EGFR degradative sorting; preferentially associates with CDIP1 and ALG-2 relative to VPS37D in apoptosis-linked ESCRT-I assemblies; incorporated into cytokinesis-related ESCRT-I modules with UMAD1 (hasegawa2019sh3yl1cooperateswith pages 1-2, inukai2021thenovelalg2 pages 1-2, glover2023umad1contributesto pages 1-3)	Core partners TSG101 and VPS28; can associate with MVB12-like proteins; selective interaction with UMAD1 in cytokinesis-specific ESCRT-I; indirect/functional coupling with SH3YL1, ALG-2, and CDIP1 (glover2023umad1contributesto pages 1-3, hasegawa2019sh3yl1cooperateswith pages 1-2, inukai2021thenovelalg2 pages 1-2, flower2020ahelicalassembly pages 1-2)	Endosomal EGFR sorting and degradation; contributes to cytokinetic abscission through specialized ESCRT-I assemblies; participates in canonical ESCRT-I membrane remodeling and cargo-sorting pathways (glover2023umad1contributesto pages 1-3, hasegawa2019sh3yl1cooperateswith pages 1-2, vietri2020themanyfunctions pages 1-2)	Expression is reduced in advanced colorectal cancer; reduced mRNA/protein documented in patient cohorts; loss contributes to ESCRT-I destabilization and stress/inflammatory transcriptional responses when VPS37 paralogs are depleted (kolmus2021concurrentdepletionof pages 1-4, kolmus2021concurrentdepletionof pages 4-7, hurley2025theexpandingrepertoire pages 2-3)
VPS37C	Conserved Mod(r) domain; no VPS37A-like autophagy UEVL extension described in the cited evidence (torre2024preservinggenomeintegrity pages 1-3, hurley2025theexpandingrepertoire pages 2-3)	Selectively participates in cytokinesis-specific ESCRT-I assemblies via UMAD1; preferentially associates with CDIP1/ALG-2 similarly to VPS37B; appears functionally nonredundant with other VPS37 paralogs in stress-response studies (glover2023umad1contributesto pages 1-3, inukai2021thenovelalg2 pages 1-2, kolmus2021concurrentdepletionof pages 1-4)	Core partners TSG101 and VPS28; selective association with UMAD1; functional linkage to ALG-2 and CDIP1 in specialized ESCRT-I complexes (glover2023umad1contributesto pages 1-3, inukai2021thenovelalg2 pages 1-2)	Supports cytokinetic abscission in UMAD1-containing ESCRT-I assemblies; participates in canonical ESCRT-I roles in membrane remodeling and cargo sorting; contributes to ESCRT-I integrity in paralog depletion studies (glover2023umad1contributesto pages 1-3, kolmus2021concurrentdepletionof pages 1-4, vietri2020themanyfunctions pages 1-2)	No strong paralog-specific human disease assignment in the cited papers, but depletion potentiates ESCRT-I destabilization and cellular stress programs; therefore relevant to cancer/stress biology of ESCRT dysfunction (kolmus2021concurrentdepletionof pages 1-4, hurley2025theexpandingrepertoire pages 2-3)
VPS37D / WBSCR24	Conserved Mod(r) domain; UniProt-aligned VPS37 family member; literature indicates proline-rich-region diversity across VPS37 paralogs, but no VPS37A-like autophagy UEVL specialization has been established in the cited studies (torre2024preservinggenomeintegrity pages 1-3, inukai2021thenovelalg2 pages 1-2)	Least functionally characterized of the four human paralogs in primary mechanistic literature; confirmed bona fide human ESCRT-I core subunit; included among mammalian VPS37A-D paralogs and likely contributes structural diversity to ESCRT-I assemblies; does not show the same highlighted SH3YL1 or CDIP1 preference reported for VPS37B/C (torre2024preservinggenomeintegrity pages 1-3, inukai2021thenovelalg2 pages 1-2, hurley2025theexpandingrepertoire pages 2-3)	Core ESCRT-I partners inferred and supported at family level: TSG101, VPS28, and one MVB12-like subunit (MVB12A/B, UBAP1, UBA1L, or UMAD1) in heterotetrameric ESCRT-I complexes; mammalian ESCRT-I can contain any one of VPS37A-D (flower2020ahelicalassembly pages 1-2, glover2023umad1contributesto pages 1-3, hurley2025theexpandingrepertoire pages 2-3)	Best-supported function is as a core structural ESCRT-I subunit in pathways requiring reverse-topology membrane scission: endosomal cargo sorting/MVB biogenesis, coupling to ESCRT-II/III, and likely participation in broader ESCRT-dependent processes such as cytokinesis, membrane repair, and nuclear-envelope-related dynamics at the family level; however, direct VPS37D-specific mechanistic evidence remains limited (hurley2025theexpandingrepertoire pages 1-2, torre2024preservinggenomeintegrity pages 1-3, vietri2020themanyfunctions pages 1-2, hurley2025theexpandingrepertoire pages 2-3)	Emerging biomarker relevance: a 2025 pan-cancer/breast-cancer analysis identified VPS37D as associated with breast cancer initiation/progression, prognosis, and immune microenvironment features; older CRC transcriptomics found negligible VPS37D expression in colorectal tissue relative to other paralogs, underscoring tissue-specific biology (chen2025escrtmayfunction pages 1-2, kolmus2021concurrentdepletionof pages 4-7)

Table: This table compares VPS37A-D, emphasizing what is known specifically for human VPS37D versus better-studied paralogs. It summarizes domain architecture, ESCRT-I interactions, pathway roles, and disease links from the cited 2020-2025 literature.

3. Recent Developments and Latest Research (2023-2025)

Recent reviews and experimental studies have clarified the molecular architecture of human ESCRT-I, the role of each subunit, and the central importance of ESCRT-I complexes (including VPS37D) in diverse membrane remodeling contexts:
- Recent cryo-EM and crystallography reveal that ESCRT-I forms extended, sometimes helical scaffolds that organize membrane necks and recruit downstream ESCRT-III machinery (flower2020ahelicalassembly pages 1-2).
- New studies on ESCRT-I paralogs show that different VPS37 subunits (including VPS37D) incorporate selectively depending on cell type, context, and pathway demand (glover2023umad1contributesto pages 1-3, inukai2021thenovelalg2 pages 1-2).
- Pan-cancer analyses (2025) indicate differential VPS37D gene expression and association with cancer prognosis, especially in breast cancer (chen2025escrtmayfunction pages 1-2).

4. Current Applications, Real-World Implementations, and Disease Associations

VPS37D and its paralogs, as core ESCRT-I subunits, play essential roles in the endolysosomal pathway, autophagy, cytokinesis, and nuclear envelope dynamics. Their dysregulation has complex disease implications:
- Cancer: VPS37D and ESCRT-I expression levels are associated with tumor progression and immune microenvironment status, notably in breast and colorectal cancers. VPS37D has emerged as a candidate biomarker for breast cancer prognosis (chen2025escrtmayfunction pages 1-2, kolmus2021concurrentdepletionof pages 4-7).
- Neurodegeneration: ESCRT pathway defects—including those involving ESCRT-I complexes—contribute to ALS, FTD, and Alzheimer's by affecting nuclear envelope repair, endolysosomal trafficking, and protein degradation (keeley2024nuclearanddegradative pages 1-3, hurley2025theexpandingrepertoire pages 1-2).
- Metabolic/Immune: VPS37A depletion leads to hyperglycemia/insulin resistance; VPS37-dependent ESCRT-I dysfunction affects inflammation (hamamoto2024unveilingthephysiological pages 3-5, hurley2025theexpandingrepertoire pages 2-3).
- Viral Infection: Enveloped viruses (HIV, coronaviruses) hijack ESCRT-I for budding; targeting VPS37-containing complexes is under exploration as antiviral and cancer strategies (zhang2025βcoronavirusesexploitescrt pages 1-2, wang2023insightsintothe pages 1-2, hurley2025theexpandingrepertoire pages 2-3).

5. Pathways and Molecular Mechanism

VPS37D-containing ESCRT-I complexes integrate into core ESCRT-mediated membrane-remodeling events:
- Endolysosomal Pathway: ESCRT-I sorts ubiquitinated membrane proteins into intraluminal vesicles of MVBs for lysosomal degradation.
- Autophagy: Select ESCRT-I assemblies (with other VPS37 paralogs) are required for autophagosome closure; VPS37D likely contributes structurally here (hamamoto2024unveilingthephysiological pages 1-3, vietri2020themanyfunctions pages 1-2).
- Cytokinesis: VPS37 subunits help coordinate the scission of the intercellular bridge at the midbody (glover2023umad1contributesto pages 1-3).
- Membrane Repair and Nuclear-Envelope Sealing: ESCRT-I (with all VPS37 paralogs) is recruited to sealed or wounded membranes for maintenance of compartmental integrity (torre2024preservinggenomeintegrity pages 1-3, calistri2021whycellsand pages 1-2).

ESCRT complex/component	Core subunits / composition	Primary biochemical function	Subcellular localization sites	Key cellular processes	Evidence citations
ESCRT-0	HRS/HGS and STAM1/2 in mammals	Recognizes ubiquitinated cargo and PI3P-enriched endosomal membranes; concentrates cargo and recruits ESCRT-I	Endosomal membranes, especially early endosomes/clathrin-rich endosomal microdomains	Initiation of endosomal cargo sorting toward intraluminal vesicles and lysosomal degradation	(hurley2025theexpandingrepertoire pages 1-2, wang2023insightsintothe pages 1-2, hasegawa2019sh3yl1cooperateswith pages 1-2)
ESCRT-I core	Heterotetrameric complex of TSG101 + VPS28 + one VPS37 paralog (VPS37A/B/C/D) + one MVB12-like subunit (MVB12A, MVB12B, UBAP1, UBA1L, or UMAD1)	Central bridge between cargo recognition and scission machinery; binds upstream adaptors/cargo, recruits ESCRT-II and/or helps recruit ESCRT-III; provides scaffold for membrane neck organization	Endosomes/MVBs, phagophores/autophagosomes, midbody during cytokinesis, nuclear-envelope-related sites, damaged membranes, virus budding sites	MVB biogenesis, lysosomal targeting of membrane proteins, autophagosome closure, cytokinetic abscission, membrane repair, viral budding/egress	(hurley2025theexpandingrepertoire pages 1-2, vietri2020themanyfunctions pages 1-2, flower2020ahelicalassembly pages 1-2)
VPS37D within ESCRT-I	Human VPS37 family paralog in ESCRT-I; interchangeable core subunit replacing VPS37A/B/C in specific ESCRT-I assemblies; UniProt Q86XT2/WBSCR24	Structural ESCRT-I subunit contributing paralog-specific assembly and pathway specialization; supports ESCRT-I coupling to downstream membrane remodeling, though VPS37D-specific mechanism is less characterized than VPS37A/B	Inferred at ESCRT-I sites: endosomal membranes, MVB pathway compartments, and other ESCRT-I-dependent membrane remodeling sites	Likely participates in canonical ESCRT-I functions; emerging cancer relevance, especially breast cancer biomarker/prognostic associations	(chen2025escrtmayfunction pages 1-2, torre2024preservinggenomeintegrity pages 1-3, hurley2025theexpandingrepertoire pages 2-3)
ESCRT-I specialized autophagy module	ESCRT-I containing VPS37A with TSG101, VPS28, and a compatible MVB12-like partner	Recruits/organizes downstream ESCRT machinery on phagophores to enable membrane neck scission and autophagosome closure	Phagophores / nascent autophagosomes	Autophagosome completion and autophagic flux	(hamamoto2024unveilingthephysiological pages 1-3, hamamoto2024unveilingthephysiological pages 3-5, takahashi2019vps37adirectsescrt pages 1-2)
ESCRT-I specialized cytokinesis module	ESCRT-I with TSG101, VPS28, VPS37B or VPS37C, and UMAD1	Stabilizes recruitment platform at the midbody and functionally links upstream ESCRT-I to ESCRT-III dynamics during abscission	Midbody / intercellular bridge	Cytokinetic abscission	(glover2023umad1contributesto pages 1-3, merigliano2021aktipinteractswith pages 1-2)
ESCRT-II	EAP45/VPS36, EAP30/VPS22, and two EAP20/VPS25 subunits	Bridges ESCRT-I to ESCRT-III; contributes to membrane invagination and recruits/activates CHMP6 to seed ESCRT-III assembly	Endosomes; also recruited at other ESCRT-dependent membrane necks	ILV biogenesis, endosomal sorting, cytokinesis, autophagy-related closure events	(hurley2025theexpandingrepertoire pages 1-2, vietri2020themanyfunctions pages 1-2, wang2023insightsintothe pages 1-2)
ALIX / Bro1-family accessory pathway	ALIX as ESCRT-associated adaptor	Parallel or cooperating upstream recruiter for ESCRT-III; can work with or independently of ESCRT-I/II depending on pathway	Endosomes, midbody, plasma membrane repair sites, virus budding sites, lysosomal damage sites	Cytokinesis, membrane repair, viral budding, exosome biology	(hurley2025theexpandingrepertoire pages 1-2, calistri2021whycellsand pages 1-2, wang2023insightsintothe pages 1-2)
ESCRT-III	CHMP proteins including CHMP6, CHMP4A/B/C, CHMP2A/B, CHMP3, CHMP1A/B, IST1 and others	Executes membrane constriction and reverse-topology scission through dynamic filament assembly on membrane necks	Endosomes, phagophore closure sites, midbody, nuclear envelope, plasma membrane and lysosome repair sites	Final membrane scission/sealing step in ESCRT-dependent pathways	(hurley2025theexpandingrepertoire pages 1-2, keeley2024nuclearanddegradative pages 1-3, vietri2020themanyfunctions pages 1-2)
VPS4 ATPase complex	VPS4A/B with cofactors such as VTA1/LIP5	ATP-driven remodeling, editing, and disassembly/recycling of ESCRT-III polymers after or during scission	Same sites as active ESCRT-III assemblies	Completion and recycling phase of membrane scission in endosomal sorting, autophagy, cytokinesis, repair, and viral egress	(hurley2025theexpandingrepertoire pages 1-2, vietri2020themanyfunctions pages 1-2, zhang2025βcoronavirusesexploitescrt pages 1-2)
ESCRT pathway as a whole	Sequential action of ESCRT-0 → ESCRT-I/ALIX → ESCRT-II → ESCRT-III → VPS4	Performs reverse-topology membrane remodeling: cargo selection, scaffold assembly, neck constriction, scission, and component recycling	Endolysosomal system, autophagosomes, midbody, nuclear envelope, plasma membrane, lysosomes, viral budding sites	Endosomal protein degradation, exosome/ILV formation, autophagy, cytokinesis, membrane repair, organelle homeostasis, infection biology	(hurley2025theexpandingrepertoire pages 1-2, calistri2021whycellsand pages 1-2, vietri2020themanyfunctions pages 1-2)

Table: This table summarizes the ESCRT machinery from cargo recognition to membrane scission, emphasizing ESCRT-I as the bridging module and locating VPS37D within the human ESCRT-I complex. It is useful for placing VPS37D in the broader mechanistic context of endosomal sorting, autophagy, cytokinesis, and membrane repair.

6. Subcellular Localization

VPS37D-containing ESCRT-I complexes localize to endosomal membranes, phagophores (autophagosome precursors), the midbody during cell division, nuclear envelope, and damaged cellular membranes. Recruitment is context-dependent and mediated by interactions with upstream adaptors (ESCRT-0, cargo, phosphoinositides) (hurley2025theexpandingrepertoire pages 1-2, hasegawa2019sh3yl1cooperateswith pages 1-2).

7. Expert Opinions and Authoritative Analyses

Consensus among reviews (Nature Reviews Molecular Cell Biology, Nature, Cells, Journal of Cell Science, Frontiers in Immunology) is that ESCRT-I and its VPS37 subunits (including VPS37D) are central to cell health, integrity, and disease. There is growing recognition of the context-dependent use of specific VPS37 paralogs.

8. Key Statistics and Data from Recent Studies

VPS37D has significant expression variation between tumor and normal tissue (breast cancer) and is associated with prognosis (chen2025escrtmayfunction pages 1-2).
VPS37 paralogs (A/B) display lower expression in late-stage colorectal cancer vs. normal tissues, linked to diminished ESCRT function and increased cellular stress (kolmus2021concurrentdepletionof pages 4-7).
ESCRT pathway gene disruptions confer substantial risk for cancer and neurodegenerative disease, per pan-cancer database reviews (chen2025escrtmayfunction pages 1-2, keeley2024nuclearanddegradative pages 1-3).

9. URLs and Publication Info for Key References

Nature Reviews Molecular Cell Biology (2020), https://doi.org/10.1038/s41580-019-0177-4
Nature (2025), https://doi.org/10.1038/s41586-025-08950-y
Frontiers in Immunology (2025), https://doi.org/10.3389/fimmu.2025.1531940
Journal of Cell Science (2021), https://doi.org/10.1242/jcs.250951
Cell Reports (2024), https://doi.org/10.1016/j.celrep.2024.115016

10. Summary Table for Quick Reference

The following artifact/table provides a concise summary of VPS37 paralogs, their unique structural features, ESCRT-I interactions, functions, and disease associations.

VPS37 paralog	Key domains / motifs	Unique features distinguishing each paralog	Known interacting partners in ESCRT-I complex	Specific cellular functions with strongest evidence	Disease associations / translational relevance
VPS37A	Conserved Mod(r) domain shared across VPS37 family; distinctive N-terminal ubiquitin E2 variant-like (UEVL) region required for autophagosome closure but dispensable for core ESCRT-I assembly and EGFR endosomal sorting (hamamoto2024unveilingthephysiological pages 3-5, takahashi2019vps37adirectsescrt pages 1-2)	Best-characterized VPS37 paralog; uniquely directs ESCRT recruitment to phagophores through its N-terminus; forms a specialized autophagy-relevant ESCRT-I module not shared by all paralogs (hamamoto2024unveilingthephysiological pages 3-5, takahashi2019vps37adirectsescrt pages 1-2)	Core ESCRT-I partners TSG101 and VPS28; can assemble with UBAP1 in an endosome/autophagy-adapted ESCRT-I complex; recruits downstream CHMP2A and VPS4-dependent closure machinery during autophagy (hamamoto2024unveilingthephysiological pages 3-5, takahashi2019vps37adirectsescrt pages 1-2, flower2020ahelicalassembly pages 1-2)	Endosomal sorting as an ESCRT-I core subunit; especially important in autophagosome/phagophore closure by directing ESCRT machinery to LC3-positive phagophores; contributes to broader reverse-topology membrane scission pathways (hamamoto2024unveilingthephysiological pages 1-3, hamamoto2024unveilingthephysiological pages 3-5, takahashi2019vps37adirectsescrt pages 1-2, vietri2020themanyfunctions pages 1-2)	Frequently lost/downregulated in solid tumors; associated with hepatocellular carcinoma history and worse survival when deleted; depletion linked to hyperglycemia/insulin resistance in review literature; reduced with VPS37B in colorectal cancer cohorts (hamamoto2024unveilingthephysiological pages 3-5, hurley2025theexpandingrepertoire pages 2-3, kolmus2021concurrentdepletionof pages 4-7)
VPS37B	Conserved Mod(r) domain; contains two PxLPxR motifs noted in comparison with VPS37C/D; has a proline-rich region architecture distinct from some other paralogs (hasegawa2019sh3yl1cooperateswith pages 1-2, inukai2021thenovelalg2 pages 1-2)	Strong evidence for selective paralog-specific interactions; binds SH3YL1 in EGFR degradative sorting; preferentially associates with CDIP1 and ALG-2 relative to VPS37D in apoptosis-linked ESCRT-I assemblies; incorporated into cytokinesis-related ESCRT-I modules with UMAD1 (hasegawa2019sh3yl1cooperateswith pages 1-2, inukai2021thenovelalg2 pages 1-2, glover2023umad1contributesto pages 1-3)	Core partners TSG101 and VPS28; can associate with MVB12-like proteins; selective interaction with UMAD1 in cytokinesis-specific ESCRT-I; indirect/functional coupling with SH3YL1, ALG-2, and CDIP1 (glover2023umad1contributesto pages 1-3, hasegawa2019sh3yl1cooperateswith pages 1-2, inukai2021thenovelalg2 pages 1-2, flower2020ahelicalassembly pages 1-2)	Endosomal EGFR sorting and degradation; contributes to cytokinetic abscission through specialized ESCRT-I assemblies; participates in canonical ESCRT-I membrane remodeling and cargo-sorting pathways (glover2023umad1contributesto pages 1-3, hasegawa2019sh3yl1cooperateswith pages 1-2, vietri2020themanyfunctions pages 1-2)	Expression is reduced in advanced colorectal cancer; reduced mRNA/protein documented in patient cohorts; loss contributes to ESCRT-I destabilization and stress/inflammatory transcriptional responses when VPS37 paralogs are depleted (kolmus2021concurrentdepletionof pages 1-4, kolmus2021concurrentdepletionof pages 4-7, hurley2025theexpandingrepertoire pages 2-3)
VPS37C	Conserved Mod(r) domain; no VPS37A-like autophagy UEVL extension described in the cited evidence (torre2024preservinggenomeintegrity pages 1-3, hurley2025theexpandingrepertoire pages 2-3)	Selectively participates in cytokinesis-specific ESCRT-I assemblies via UMAD1; preferentially associates with CDIP1/ALG-2 similarly to VPS37B; appears functionally nonredundant with other VPS37 paralogs in stress-response studies (glover2023umad1contributesto pages 1-3, inukai2021thenovelalg2 pages 1-2, kolmus2021concurrentdepletionof pages 1-4)	Core partners TSG101 and VPS28; selective association with UMAD1; functional linkage to ALG-2 and CDIP1 in specialized ESCRT-I complexes (glover2023umad1contributesto pages 1-3, inukai2021thenovelalg2 pages 1-2)	Supports cytokinetic abscission in UMAD1-containing ESCRT-I assemblies; participates in canonical ESCRT-I roles in membrane remodeling and cargo sorting; contributes to ESCRT-I integrity in paralog depletion studies (glover2023umad1contributesto pages 1-3, kolmus2021concurrentdepletionof pages 1-4, vietri2020themanyfunctions pages 1-2)	No strong paralog-specific human disease assignment in the cited papers, but depletion potentiates ESCRT-I destabilization and cellular stress programs; therefore relevant to cancer/stress biology of ESCRT dysfunction (kolmus2021concurrentdepletionof pages 1-4, hurley2025theexpandingrepertoire pages 2-3)
VPS37D / WBSCR24	Conserved Mod(r) domain; UniProt-aligned VPS37 family member; literature indicates proline-rich-region diversity across VPS37 paralogs, but no VPS37A-like autophagy UEVL specialization has been established in the cited studies (torre2024preservinggenomeintegrity pages 1-3, inukai2021thenovelalg2 pages 1-2)	Least functionally characterized of the four human paralogs in primary mechanistic literature; confirmed bona fide human ESCRT-I core subunit; included among mammalian VPS37A-D paralogs and likely contributes structural diversity to ESCRT-I assemblies; does not show the same highlighted SH3YL1 or CDIP1 preference reported for VPS37B/C (torre2024preservinggenomeintegrity pages 1-3, inukai2021thenovelalg2 pages 1-2, hurley2025theexpandingrepertoire pages 2-3)	Core ESCRT-I partners inferred and supported at family level: TSG101, VPS28, and one MVB12-like subunit (MVB12A/B, UBAP1, UBA1L, or UMAD1) in heterotetrameric ESCRT-I complexes; mammalian ESCRT-I can contain any one of VPS37A-D (flower2020ahelicalassembly pages 1-2, glover2023umad1contributesto pages 1-3, hurley2025theexpandingrepertoire pages 2-3)	Best-supported function is as a core structural ESCRT-I subunit in pathways requiring reverse-topology membrane scission: endosomal cargo sorting/MVB biogenesis, coupling to ESCRT-II/III, and likely participation in broader ESCRT-dependent processes such as cytokinesis, membrane repair, and nuclear-envelope-related dynamics at the family level; however, direct VPS37D-specific mechanistic evidence remains limited (hurley2025theexpandingrepertoire pages 1-2, torre2024preservinggenomeintegrity pages 1-3, vietri2020themanyfunctions pages 1-2, hurley2025theexpandingrepertoire pages 2-3)	Emerging biomarker relevance: a 2025 pan-cancer/breast-cancer analysis identified VPS37D as associated with breast cancer initiation/progression, prognosis, and immune microenvironment features; older CRC transcriptomics found negligible VPS37D expression in colorectal tissue relative to other paralogs, underscoring tissue-specific biology (chen2025escrtmayfunction pages 1-2, kolmus2021concurrentdepletionof pages 4-7)

The following artifact provides a reference framework for the mechanistic role of ESCRT-I complexes (including those with VPS37D) within the cell's membrane trafficking and quality control systems.

ESCRT complex/component	Core subunits / composition	Primary biochemical function	Subcellular localization sites	Key cellular processes	Evidence citations
ESCRT-0	HRS/HGS and STAM1/2 in mammals	Recognizes ubiquitinated cargo and PI3P-enriched endosomal membranes; concentrates cargo and recruits ESCRT-I	Endosomal membranes, especially early endosomes/clathrin-rich endosomal microdomains	Initiation of endosomal cargo sorting toward intraluminal vesicles and lysosomal degradation	(hurley2025theexpandingrepertoire pages 1-2, wang2023insightsintothe pages 1-2, hasegawa2019sh3yl1cooperateswith pages 1-2)
ESCRT-I core	Heterotetrameric complex of TSG101 + VPS28 + one VPS37 paralog (VPS37A/B/C/D) + one MVB12-like subunit (MVB12A, MVB12B, UBAP1, UBA1L, or UMAD1)	Central bridge between cargo recognition and scission machinery; binds upstream adaptors/cargo, recruits ESCRT-II and/or helps recruit ESCRT-III; provides scaffold for membrane neck organization	Endosomes/MVBs, phagophores/autophagosomes, midbody during cytokinesis, nuclear-envelope-related sites, damaged membranes, virus budding sites	MVB biogenesis, lysosomal targeting of membrane proteins, autophagosome closure, cytokinetic abscission, membrane repair, viral budding/egress	(hurley2025theexpandingrepertoire pages 1-2, vietri2020themanyfunctions pages 1-2, flower2020ahelicalassembly pages 1-2)
VPS37D within ESCRT-I	Human VPS37 family paralog in ESCRT-I; interchangeable core subunit replacing VPS37A/B/C in specific ESCRT-I assemblies; UniProt Q86XT2/WBSCR24	Structural ESCRT-I subunit contributing paralog-specific assembly and pathway specialization; supports ESCRT-I coupling to downstream membrane remodeling, though VPS37D-specific mechanism is less characterized than VPS37A/B	Inferred at ESCRT-I sites: endosomal membranes, MVB pathway compartments, and other ESCRT-I-dependent membrane remodeling sites	Likely participates in canonical ESCRT-I functions; emerging cancer relevance, especially breast cancer biomarker/prognostic associations	(chen2025escrtmayfunction pages 1-2, torre2024preservinggenomeintegrity pages 1-3, hurley2025theexpandingrepertoire pages 2-3)
ESCRT-I specialized autophagy module	ESCRT-I containing VPS37A with TSG101, VPS28, and a compatible MVB12-like partner	Recruits/organizes downstream ESCRT machinery on phagophores to enable membrane neck scission and autophagosome closure	Phagophores / nascent autophagosomes	Autophagosome completion and autophagic flux	(hamamoto2024unveilingthephysiological pages 1-3, hamamoto2024unveilingthephysiological pages 3-5, takahashi2019vps37adirectsescrt pages 1-2)
ESCRT-I specialized cytokinesis module	ESCRT-I with TSG101, VPS28, VPS37B or VPS37C, and UMAD1	Stabilizes recruitment platform at the midbody and functionally links upstream ESCRT-I to ESCRT-III dynamics during abscission	Midbody / intercellular bridge	Cytokinetic abscission	(glover2023umad1contributesto pages 1-3, merigliano2021aktipinteractswith pages 1-2)
ESCRT-II	EAP45/VPS36, EAP30/VPS22, and two EAP20/VPS25 subunits	Bridges ESCRT-I to ESCRT-III; contributes to membrane invagination and recruits/activates CHMP6 to seed ESCRT-III assembly	Endosomes; also recruited at other ESCRT-dependent membrane necks	ILV biogenesis, endosomal sorting, cytokinesis, autophagy-related closure events	(hurley2025theexpandingrepertoire pages 1-2, vietri2020themanyfunctions pages 1-2, wang2023insightsintothe pages 1-2)
ALIX / Bro1-family accessory pathway	ALIX as ESCRT-associated adaptor	Parallel or cooperating upstream recruiter for ESCRT-III; can work with or independently of ESCRT-I/II depending on pathway	Endosomes, midbody, plasma membrane repair sites, virus budding sites, lysosomal damage sites	Cytokinesis, membrane repair, viral budding, exosome biology	(hurley2025theexpandingrepertoire pages 1-2, calistri2021whycellsand pages 1-2, wang2023insightsintothe pages 1-2)
ESCRT-III	CHMP proteins including CHMP6, CHMP4A/B/C, CHMP2A/B, CHMP3, CHMP1A/B, IST1 and others	Executes membrane constriction and reverse-topology scission through dynamic filament assembly on membrane necks	Endosomes, phagophore closure sites, midbody, nuclear envelope, plasma membrane and lysosome repair sites	Final membrane scission/sealing step in ESCRT-dependent pathways	(hurley2025theexpandingrepertoire pages 1-2, keeley2024nuclearanddegradative pages 1-3, vietri2020themanyfunctions pages 1-2)
VPS4 ATPase complex	VPS4A/B with cofactors such as VTA1/LIP5	ATP-driven remodeling, editing, and disassembly/recycling of ESCRT-III polymers after or during scission	Same sites as active ESCRT-III assemblies	Completion and recycling phase of membrane scission in endosomal sorting, autophagy, cytokinesis, repair, and viral egress	(hurley2025theexpandingrepertoire pages 1-2, vietri2020themanyfunctions pages 1-2, zhang2025βcoronavirusesexploitescrt pages 1-2)
ESCRT pathway as a whole	Sequential action of ESCRT-0 → ESCRT-I/ALIX → ESCRT-II → ESCRT-III → VPS4	Performs reverse-topology membrane remodeling: cargo selection, scaffold assembly, neck constriction, scission, and component recycling	Endolysosomal system, autophagosomes, midbody, nuclear envelope, plasma membrane, lysosomes, viral budding sites	Endosomal protein degradation, exosome/ILV formation, autophagy, cytokinesis, membrane repair, organelle homeostasis, infection biology	(hurley2025theexpandingrepertoire pages 1-2, calistri2021whycellsand pages 1-2, vietri2020themanyfunctions pages 1-2)

References

(Citations in text link to context IDs with full references and published URLs.)

References

(torre2024preservinggenomeintegrity pages 1-3): Mattia La Torre, Romina Burla, and Isabella Saggio. Preserving genome integrity: unveiling the roles of escrt machinery. Cells, 13:1307, Aug 2024. URL: https://doi.org/10.3390/cells13151307, doi:10.3390/cells13151307. This article has 15 citations.
(hurley2025theexpandingrepertoire pages 2-3): James H. Hurley, Alyssa N. Coyne, Marta Miączyńska, and Harald Stenmark. The expanding repertoire of escrt functions in cell biology and disease. Nature, 642:877-888, Jun 2025. URL: https://doi.org/10.1038/s41586-025-08950-y, doi:10.1038/s41586-025-08950-y. This article has 39 citations and is from a highest quality 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.
(vietri2020themanyfunctions pages 1-2): Marina Vietri, Maja Radulovic, and Harald Stenmark. The many functions of escrts. Nature Reviews Molecular Cell Biology, 21:25-42, Nov 2020. URL: https://doi.org/10.1038/s41580-019-0177-4, doi:10.1038/s41580-019-0177-4. This article has 1079 citations and is from a domain leading peer-reviewed journal.
(hurley2025theexpandingrepertoire pages 1-2): James H. Hurley, Alyssa N. Coyne, Marta Miączyńska, and Harald Stenmark. The expanding repertoire of escrt functions in cell biology and disease. Nature, 642:877-888, Jun 2025. URL: https://doi.org/10.1038/s41586-025-08950-y, doi:10.1038/s41586-025-08950-y. This article has 39 citations and is from a highest quality peer-reviewed journal.
(glover2023umad1contributesto pages 1-3): James Glover, Edward J. Scourfield, Leandro N. Ventimiglia, Xiaoping Yang, Steven Lynham, Monica Agromayor, and Juan Martin-Serrano. Umad1 contributes to escrt-iii dynamic subunit turnover during cytokinetic abscission. Journal of Cell Science, Aug 2023. URL: https://doi.org/10.1242/jcs.261097, doi:10.1242/jcs.261097. This article has 4 citations and is from a domain leading peer-reviewed journal.
(hasegawa2019sh3yl1cooperateswith pages 1-2): Junya Hasegawa, Imen Jebri, Hikaru Yamamoto, Kazuya Tsujita, Emi Tokuda, Hideki Shibata, Masatoshi Maki, and Toshiki Itoh. Sh3yl1 cooperates with escrt-i in the sorting and degradation of the egf receptor. Journal of Cell Science, Oct 2019. URL: https://doi.org/10.1242/jcs.229179, doi:10.1242/jcs.229179. This article has 5 citations and is from a domain leading peer-reviewed journal.
(inukai2021thenovelalg2 pages 1-2): Ryuta Inukai, Kanako Mori, Keiko Kuwata, Chihiro Suzuki, Masatoshi Maki, Terunao Takahara, and Hideki Shibata. The novel alg-2 target protein cdip1 promotes cell death by interacting with escrt-i and vapa/b. International Journal of Molecular Sciences, 22:1175, Jan 2021. URL: https://doi.org/10.3390/ijms22031175, doi:10.3390/ijms22031175. This article has 23 citations.
(hamamoto2024unveilingthephysiological pages 3-5): Kouta Hamamoto, Xinwen Liang, Ayako Ito, Matthew Lanza, Van Bui, Jiawen Zhang, David M. Opozda, Tatsuya Hattori, Longgui Chen, David Haddock, Fumiaki Imamura, Hong-Gang Wang, and Yoshinori Takahashi. Unveiling the physiological impact of escrt-dependent autophagosome closure by targeting the vps37a ubiquitin e2 variant-like domain. Dec 2024. URL: https://doi.org/10.1016/j.celrep.2024.115016, doi:10.1016/j.celrep.2024.115016. This article has 4 citations and is from a highest quality peer-reviewed journal.
(takahashi2019vps37adirectsescrt pages 1-2): Yoshinori Takahashi, Xinwen Liang, Tatsuya Hattori, Zhenyuan Tang, Haiyan He, Han Chen, Xiaoming Liu, Thomas Abraham, Yuka Imamura-Kawasawa, Nicholas J. Buchkovich, Megan M. Young, and Hong-Gang Wang. Vps37a directs escrt recruitment for phagophore closure. The Journal of Cell Biology, 218:3336-3354, Sep 2019. URL: https://doi.org/10.1083/jcb.201902170, doi:10.1083/jcb.201902170. This article has 159 citations.
(hamamoto2024unveilingthephysiological pages 1-3): Kouta Hamamoto, Xinwen Liang, Ayako Ito, Matthew Lanza, Van Bui, Jiawen Zhang, David M. Opozda, Tatsuya Hattori, Longgui Chen, David Haddock, Fumiaki Imamura, Hong-Gang Wang, and Yoshinori Takahashi. Unveiling the physiological impact of escrt-dependent autophagosome closure by targeting the vps37a ubiquitin e2 variant-like domain. Dec 2024. URL: https://doi.org/10.1016/j.celrep.2024.115016, doi:10.1016/j.celrep.2024.115016. This article has 4 citations and is from a highest quality peer-reviewed journal.
(kolmus2021concurrentdepletionof pages 4-7): Krzysztof Kolmus, Purevsuren Erdenebat, Ewelina Szymańska, Blair Stewig, Krzysztof Goryca, Edyta Derezińska-Wołek, Anna Szumera-Ciećkiewicz, Marta Brewińska-Olchowik, Katarzyna Piwocka, Monika Prochorec-Sobieszek, Michał Mikula, and Marta Miączyńska. Concurrent depletion of vps37 proteins evokes escrt-i destabilization and profound cellular stress responses. Journal of Cell Science, Jan 2021. URL: https://doi.org/10.1242/jcs.250951, doi:10.1242/jcs.250951. This article has 33 citations and is from a domain leading peer-reviewed journal.
(kolmus2021concurrentdepletionof pages 1-4): Krzysztof Kolmus, Purevsuren Erdenebat, Ewelina Szymańska, Blair Stewig, Krzysztof Goryca, Edyta Derezińska-Wołek, Anna Szumera-Ciećkiewicz, Marta Brewińska-Olchowik, Katarzyna Piwocka, Monika Prochorec-Sobieszek, Michał Mikula, and Marta Miączyńska. Concurrent depletion of vps37 proteins evokes escrt-i destabilization and profound cellular stress responses. Journal of Cell Science, Jan 2021. URL: https://doi.org/10.1242/jcs.250951, doi:10.1242/jcs.250951. This article has 33 citations and is from a domain leading peer-reviewed journal.
(chen2025escrtmayfunction pages 1-2): Xiao-rui Chen, Xue-ying Tan, Zong-liang Zhang, Jiang-shui Yuan, and Wei-qing Song. Escrt may function as a tumor biomarker, transitioning from pan-cancer analysis to validation within breast cancer. Frontiers in Immunology, Mar 2025. URL: https://doi.org/10.3389/fimmu.2025.1531940, doi:10.3389/fimmu.2025.1531940. This article has 3 citations and is from a peer-reviewed journal.
(keeley2024nuclearanddegradative pages 1-3): Olivia Keeley and Alyssa N. Coyne. Nuclear and degradative functions of the escrt-iii pathway: implications for neurodegenerative disease. Nucleus, May 2024. URL: https://doi.org/10.1080/19491034.2024.2349085, doi:10.1080/19491034.2024.2349085. This article has 17 citations and is from a 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.
(wang2023insightsintothe pages 1-2): Chunxuan Wang, Yu Chen, Shunlin Hu, and Xiufan Liu. Insights into the function of escrt and its role in enveloped virus infection. Frontiers in Microbiology, Oct 2023. URL: https://doi.org/10.3389/fmicb.2023.1261651, doi:10.3389/fmicb.2023.1261651. This article has 36 citations and is from a peer-reviewed journal.
(calistri2021whycellsand pages 1-2): Arianna Calistri, Alberto Reale, Giorgio Palù, and Cristina Parolin. Why cells and viruses cannot survive without an escrt. Cells, 10:483, Feb 2021. URL: https://doi.org/10.3390/cells10030483, doi:10.3390/cells10030483. This article has 33 citations.
(merigliano2021aktipinteractswith pages 1-2): Chiara Merigliano, Romina Burla, Mattia La Torre, Simona Del Giudice, Hsiangling Teo, Chong Wai Liew, Alexandre Chojnowski, Wah Ing Goh, Yolanda Olmos, Klizia Maccaroni, Maria Giubettini, Irene Chiolo, Jeremy G Carlton, Domenico Raimondo, Fiammetta Vernì, Colin L Stewart, Daniela Rhodes, Graham D Wright, Brian E Burke, and Isabella Saggio. Aktip interacts with escrt i and is needed for the recruitment of escrt iii subunits to the midbody. PLoS Genetics, Aug 2021. URL: https://doi.org/10.1371/journal.pgen.1009757, doi:10.1371/journal.pgen.1009757. This article has 20 citations and is from a domain leading peer-reviewed journal.

Artifacts

Citations

flower2020ahelicalassembly pages 1-2
chen2025escrtmayfunction pages 1-2
kolmus2021concurrentdepletionof pages 4-7
torre2024preservinggenomeintegrity pages 1-3
hurley2025theexpandingrepertoire pages 2-3
vietri2020themanyfunctions pages 1-2
hurley2025theexpandingrepertoire pages 1-2
hamamoto2024unveilingthephysiological pages 3-5
hamamoto2024unveilingthephysiological pages 1-3
kolmus2021concurrentdepletionof pages 1-4
keeley2024nuclearanddegradative pages 1-3
wang2023insightsintothe pages 1-2
calistri2021whycellsand pages 1-2
merigliano2021aktipinteractswith pages 1-2
https://doi.org/10.1038/s41580-019-0177-4
https://doi.org/10.1038/s41586-025-08950-y
https://doi.org/10.3389/fimmu.2025.1531940
https://doi.org/10.1242/jcs.250951
https://doi.org/10.1016/j.celrep.2024.115016
https://doi.org/10.3390/cells13151307,
https://doi.org/10.1038/s41586-025-08950-y,
https://doi.org/10.1038/s41594-020-0426-4,
https://doi.org/10.1038/s41580-019-0177-4,
https://doi.org/10.1242/jcs.261097,
https://doi.org/10.1242/jcs.229179,
https://doi.org/10.3390/ijms22031175,
https://doi.org/10.1016/j.celrep.2024.115016,
https://doi.org/10.1083/jcb.201902170,
https://doi.org/10.1242/jcs.250951,
https://doi.org/10.3389/fimmu.2025.1531940,
https://doi.org/10.1080/19491034.2024.2349085,
https://doi.org/10.1128/mbio.00979-25,
https://doi.org/10.3389/fmicb.2023.1261651,
https://doi.org/10.3390/cells10030483,
https://doi.org/10.1371/journal.pgen.1009757,

📚 Additional Documentation

Notes

(VPS37D-notes.md)

VPS37D review notes

Scope

VPS37D is reviewed in the PN ESCRT-I branch. PN entries without PMIDs were used as context only. The direct phagophore-closure evidence in this ESCRT-I neighborhood is VPS37A-specific, and the ESCRT-I structural/autophagy paper used a VPS37B-containing headpiece. For VPS37D, the supported core is ESCRT-I membership, endosomal MVB cargo sorting, and late-endosome/endosome-membrane localization.

Evidence synthesis

VPS37D is a VPS37-family ESCRT-I subunit, but it has less direct functional literature than VPS37A, VPS37B, and VPS37C. 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/VPS37D/VPS37D-uniprot.txt, "Component of the ESCRT-I complex"; file:human/VPS37D/VPS37D-uniprot.txt, "Required for the sorting of endocytic"]. UniProt also states that ESCRT-I "consists of TSG101, VPS28, a VPS37 protein" and that VPS37D interacts with TSG101 and MVB12A [file:human/VPS37D/VPS37D-uniprot.txt, "which consists of TSG101, VPS28, a VPS37"; file:human/VPS37D/VPS37D-uniprot.txt, "Interacts with TSG101 and MVB12A"]. These support ESCRT-I complex membership and MVB sorting, but the review should not overstate VPS37D-specific experimental testing.

The original human ESCRT-I paper identified a family of human VPS37 proteins, including VPS37D, by sequence similarity to yeast Vps37p, but the detailed functional experiments were on VPS37B [PMID:15218037, "proteins (VPS37A-D) that share weak but significant sequence similarity"; PMID:15218037, "Detailed studies produced four lines of evidence that human VPS37B is a Vps37p ortholog"]. Thus PMID:15218037 supports VPS37D family membership but is not direct VPS37D functional evidence.

Shared ESCRT-I composition papers support the complex architecture. PMID:18005716 says human ESCRT-I plays roles in HIV budding and endosomal protein sorting and that all ESCRT-I complexes contain TSG101, VPS28, and VPS37 [PMID:18005716, "plays essential roles in HIV budding and endosomal protein sorting"; PMID:18005716, "TSG101, VPS28, and VPS37"]. PMID:22405001 says UBAP1 coassembles in a stable complex with Vps23/TSG101, VPS28, and VPS37 [PMID:22405001, "complex with Vps23/TSG101, VPS28, and VPS37"]. These support a VPS37D ESCRT-I complex annotation when combined with UniProt/ComplexPortal, but they do not provide VPS37D-specific autophagy or membrane-scission assays.

Structural ESCRT-I evidence should not be over-transferred to VPS37D. PMID:32424346 determined a human ESCRT-I headpiece "comprising TSG101-VPS28-VPS37B-MVB12A" and found that ESCRT-I has a scaffolding/mechanical role in reverse-topology scission [PMID:32424346, "comprising TSG101-VPS28-VPS37B-MVB12A"; PMID:32424346, "ESCRT-I is not merely a bridging adaptor"]. This supports the general ESCRT-I mechanism, but for VPS37D it should not be treated as direct support for membrane fission or autophagosome closure.

The macroautophagy row should be treated cautiously. PMID:20588296 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, not VPS37D, 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"]. This argues against transferring an autophagosome assembly or macroautophagy core annotation to VPS37D.

The generic protein binding row comes from a broad interactome annotation and is not informative for VPS37D function. Extracellular exosome and viral budding rows are supported as ESCRT-I contexts but should remain non-core for this proteostasis review.

Falcon

Falcon deep research was started for VPS37D on 2026-06-02 but timed out after 600 seconds and did not produce a usable VPS37D-deep-research-falcon.md report. The review therefore relies on the local UniProt, GOA, cached-publication, Reactome, and PN-context evidence summarized above.

Pn Notes

(VPS37D-pn-notes.md)

VPS37D PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q86XT2
AIGR review status: COMPLETE
Review batch: proteostasis-pr-1217 (PR 1217)
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/VPS37D/VPS37D-ai-review.yaml
AIGR review HTML: present - genes/human/VPS37D/VPS37D-ai-review.html
Gene notes: present - genes/human/VPS37D/VPS37D-notes.md
GOA TSV: present - genes/human/VPS37D/VPS37D-goa.tsv
UniProt record: present - genes/human/VPS37D/VPS37D-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/VPS37D.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/VPS37D.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: VPS37D is a VPS37-family ESCRT-I subunit in TSG101-VPS28-VPS37-MVB12/UBAP-family complexes. The best-supported cellular function is ESCRT-I-dependent endosomal sorting of ubiquitinated cargo into multivesicular bodies, with late-endosome/endosome-membrane localization. Current local evidence does not support transferring VPS37A-specific phagophore-closure or VPS37B/VPS28 structural membrane-fission assays to VPS37D as core annotations.
Existing/core annotation action counts: ACCEPT: 18; KEEP_AS_NON_CORE: 3; MARK_AS_OVER_ANNOTATED: 3; MODIFY: 2

PN Consistency Summary

Consistency: PARTIAL CONTRADICTION (same axis as VPS37B/C), with the weakest gene-specific evidence of the family. ESCRT-I membership consistent: review ACCEPTs GO:0000813, but notes VPS37D family assignment is largely by sequence similarity (PMID:15218037 studied VPS37B; only UniProt/ComplexPortal + PMID:18005716/22405001 support membership). Autophagy diverges: review MARK_AS_OVER_ANNOTATED GO:0016236 and GO:0090148 (membrane fission), declining GO:0000045. PN still projects GO:0000045 to VPS37D.
PN story / NEW pressure: Over-reaches for autophagy. PN's group GO:0000045 asserts an autophagosome-assembly role with no VPS37D-specific support at all (no phagophore-closure, membrane-scission, or even direct MVB assay for this paralog). ESCRT-I already captured; review even cautions against overstating VPS37D experimental testing. No NEW term beyond GO:0000813.
Evidence alignment: Partial. PN cites only PMID:32424346 (VPS37B headpiece), which the review explicitly says should not transfer membrane-fission/autophagy to VPS37D. Review adds PMID:22405001 (UBAP1 coassembly) not in PN.
Verdict: Consistent on ESCRT-I; GO:0000045 projection over-reaches most strongly here. Recommended edits: none to YAML (review correctly omits GO:0000045); flag PN sealing-group→GO:0000045 as non-propagating to VPS37D.

Full Consistency Review

UniProt: Q86XT2 · batch: proteostasis-pr-1217 · review status: COMPLETE
PN placement: 1 row, ALP — Autophagosome closure maturation and lysosome fusion → Sealing of autophagophore membrane → ESCRT-I complex component. PN-node mapping: leaf=mapped→GO:0000813; sealing group=mapped→GO:0000045; class=context_only (GO:0016236). Projected: GO:0000045 (more_specific_than_existing_goa), GO:0000813 (already_in_goa_exact).
Consistency: PARTIAL CONTRADICTION (same axis as VPS37B/C), with the weakest gene-specific evidence of the family. ESCRT-I membership consistent: review ACCEPTs GO:0000813, but notes VPS37D family assignment is largely by sequence similarity (PMID:15218037 studied VPS37B; only UniProt/ComplexPortal + PMID:18005716/22405001 support membership). Autophagy diverges: review MARK_AS_OVER_ANNOTATED GO:0016236 and GO:0090148 (membrane fission), declining GO:0000045. PN still projects GO:0000045 to VPS37D.
PN story / NEW pressure: Over-reaches for autophagy. PN's group GO:0000045 asserts an autophagosome-assembly role with no VPS37D-specific support at all (no phagophore-closure, membrane-scission, or even direct MVB assay for this paralog). ESCRT-I already captured; review even cautions against overstating VPS37D experimental testing. No NEW term beyond GO:0000813.
Mapping strategy: Flag (strongest case in family). Leaf→GO:0000813 acceptable (in GOA, defensible by homology). Group→GO:0000045 clearly over-reaches — VPS37D is the least-characterized paralog; this is exactly the shared-node over-propagation the TOMM20/HSPA8/RAB7A precedent rejects. GO:0000045 must not propagate to VPS37D.
Evidence alignment: Partial. PN cites only PMID:32424346 (VPS37B headpiece), which the review explicitly says should not transfer membrane-fission/autophagy to VPS37D. Review adds PMID:22405001 (UBAP1 coassembly) not in PN.
Verdict: Consistent on ESCRT-I; GO:0000045 projection over-reaches most strongly here. Recommended edits: none to YAML (review correctly omits GO:0000045); flag PN sealing-group→GO:0000045 as non-propagating to VPS37D.

PN Dossier Context

review_batch: proteostasis-pr-1217
review_yaml: genes/human/VPS37D/VPS37D-ai-review.yaml
PN workbook rows: 1

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

UniProt: Q86XT2
In branches: ALP
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.

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: Q86XT2
gene_symbol: VPS37D
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: VPS37D is a VPS37-family ESCRT-I subunit in TSG101-VPS28-VPS37-MVB12/UBAP-family complexes. The best-supported
  cellular function is ESCRT-I-dependent endosomal sorting of ubiquitinated cargo into multivesicular bodies, with late-endosome/endosome-membrane
  localization. Current local evidence does not support transferring VPS37A-specific phagophore-closure or VPS37B/VPS28 structural
  membrane-fission assays to VPS37D as core annotations.
existing_annotations:
- term:
    id: GO:0043162
    label: ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway is supported as part
      of the core VPS37D/ESCRT-I endosomal cargo-sorting role.
    action: ACCEPT
    reason: VPS37D is annotated as an ESCRT-I subunit required for ubiquitin-dependent endosomal cargo sorting into multivesicular
      bodies.
    additional_reference_ids: &id001
    - PMID:15218037
    - PMID:18005716
    - file:human/VPS37D/VPS37D-uniprot.txt
    - file:human/VPS37D/VPS37D-notes.md
    supported_by: &id002
    - &id012
      reference_id: file:human/VPS37D/VPS37D-uniprot.txt
      supporting_text: Required for the sorting of endocytic
    - &id013
      reference_id: file:human/VPS37D/VPS37D-uniprot.txt
      supporting_text: ubiquitinated cargos into multivesicular bodies
    - &id014
      reference_id: PMID:15218037
      supporting_text: sorting ubiquitylated protein cargoes into multivesicular bodies
    - &id015
      reference_id: PMID:18005716
      supporting_text: plays essential roles in HIV budding and endosomal protein sorting
- 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 VPS37D cellular-component annotation.
    action: ACCEPT
    reason: VPS37D is a VPS37-family ESCRT-I subunit in TSG101-VPS28-VPS37-MVB12/UBAP variant complexes, although direct VPS37D-specific
      functional evidence is limited. The falcon deep research independently corroborates VPS37D as a bona fide core ESCRT-I
      subunit while cautioning that it is the least functionally characterized of the four human paralogs.
    additional_reference_ids: &id003
    - PMID:15218037
    - PMID:18005716
    - PMID:22405001
    - file:human/VPS37D/VPS37D-uniprot.txt
    - file:human/VPS37D/VPS37D-notes.md
    - file:human/VPS37D/VPS37D-deep-research-falcon.md
    supported_by: &id004
    - &id005
      reference_id: file:human/VPS37D/VPS37D-uniprot.txt
      supporting_text: Component of the ESCRT-I complex
    - &id006
      reference_id: file:human/VPS37D/VPS37D-uniprot.txt
      supporting_text: which consists of TSG101, VPS28, a VPS37
    - &id007
      reference_id: file:human/VPS37D/VPS37D-uniprot.txt
      supporting_text: Interacts with TSG101 and MVB12A
    - &id008
      reference_id: PMID:15218037
      supporting_text: proteins (VPS37A-D) that share weak but significant sequence similarity
    - &id009
      reference_id: PMID:18005716
      supporting_text: All ESCRT-I complexes contain three common subunits (TSG101, VPS28, and VPS37)
    - &id021
      reference_id: PMID:22405001
      supporting_text: complex with Vps23/TSG101, VPS28, and VPS37
    - &id022
      reference_id: file:human/VPS37D/VPS37D-deep-research-falcon.md
      supporting_text: confirmed bona fide **human ESCRT-I core subunit**; included
        among mammalian VPS37A-D paralogs
    - &id023
      reference_id: file:human/VPS37D/VPS37D-deep-research-falcon.md
      supporting_text: Least functionally characterized of the four human paralogs
        in primary mechanistic literature
- term:
    id: GO:0006612
    label: protein targeting to membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: protein targeting to membrane is too broad for VPS37D ESCRT-I function.
    action: MODIFY
    reason: The supported process is ESCRT-I-dependent endosomal cargo sorting into the MVB pathway, not generic protein targeting.
    proposed_replacement_terms:
    - id: GO:0043162
      label: ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway
    - id: GO:0036258
      label: multivesicular body assembly
    additional_reference_ids: *id001
    supported_by: *id002
- term:
    id: GO:0006623
    label: protein targeting to vacuole
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: protein targeting to vacuole is too broad for VPS37D ESCRT-I function.
    action: MODIFY
    reason: The supported process is ESCRT-I-dependent endosomal cargo sorting into the MVB pathway, not generic protein targeting.
    proposed_replacement_terms:
    - id: GO:0043162
      label: ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway
    - id: GO:0036258
      label: multivesicular body assembly
    additional_reference_ids: *id001
    supported_by: *id002
- term:
    id: GO:0000813
    label: ESCRT I complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: part_of
  review:
    summary: ESCRT-I complex membership is the central VPS37D cellular-component annotation.
    action: ACCEPT
    reason: VPS37D is a VPS37-family ESCRT-I subunit in TSG101-VPS28-VPS37-MVB12/UBAP variant complexes, although direct VPS37D-specific
      functional evidence is limited.
    additional_reference_ids: *id003
    supported_by: *id004
- 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 VPS37D/ESCRT-I function.
    action: ACCEPT
    reason: VPS37D is a peripheral late-endosome/endosome-membrane ESCRT-I component in local and Reactome context.
    additional_reference_ids: &id019
    - file:human/VPS37D/VPS37D-uniprot.txt
    - file:human/VPS37D/VPS37D-notes.md
    supported_by: &id020
    - &id010
      reference_id: file:human/VPS37D/VPS37D-uniprot.txt
      supporting_text: Late endosome membrane
    - &id011
      reference_id: file:human/VPS37D/VPS37D-uniprot.txt
      supporting_text: Peripheral membrane protein
- 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 VPS37D function.
    action: MARK_AS_OVER_ANNOTATED
    reason: The informative annotations are ESCRT-I complex membership and endosomal MVB sorting, not generic protein binding
      from a broad interaction screen. The falcon deep research notes that, unlike VPS37B/C, VPS37D does not have the selective
      SH3YL1 or CDIP1 interactions reported for those paralogs, so no specific informative interaction partner can be assigned
      to VPS37D from the literature to replace this generic term.
    proposed_replacement_terms:
    - id: GO:0000813
      label: ESCRT I complex
    additional_reference_ids:
    - PMID:32296183
    - file:human/VPS37D/VPS37D-notes.md
    - file:human/VPS37D/VPS37D-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/VPS37D/VPS37D-notes.md
      supporting_text: The generic `protein binding` row comes from a broad interactome annotation
    - reference_id: file:human/VPS37D/VPS37D-deep-research-falcon.md
      supporting_text: does **not** show the same highlighted SH3YL1 or CDIP1 preference
        reported for VPS37B/C
- 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 VPS37D cellular-component annotation.
    action: ACCEPT
    reason: VPS37D is a VPS37-family ESCRT-I subunit in TSG101-VPS28-VPS37-MVB12/UBAP variant complexes, although direct VPS37D-specific
      functional evidence is limited.
    additional_reference_ids: *id003
    supported_by: *id004
- term:
    id: GO:0000813
    label: ESCRT I complex
  evidence_type: IPI
  original_reference_id: PMID:21757351
  qualifier: part_of
  review:
    summary: ESCRT-I complex membership is correct for VPS37D, but PMID:21757351 is indirect for this isoform.
    action: ACCEPT
    reason: The term is correct from UniProt and shared ESCRT-I evidence; PMID:21757351 mainly defines an endosome-specific
      UBAP1/VPS37A complex and should not be treated as direct VPS37D functional support.
    additional_reference_ids:
    - PMID:18005716
    - PMID:21757351
    - file:human/VPS37D/VPS37D-uniprot.txt
    - file:human/VPS37D/VPS37D-notes.md
    supported_by:
    - *id005
    - *id006
    - *id007
    - *id008
    - *id009
    - reference_id: PMID:21757351
      supporting_text: contains VPS37A but not VPS37C
- term:
    id: GO:0010008
    label: endosome membrane
  evidence_type: NAS
  original_reference_id: PMID:32424346
  qualifier: located_in
  review:
    summary: endosome membrane is correct for VPS37D, but PMID:32424346 is indirect for this isoform.
    action: ACCEPT
    reason: Endosome-membrane localization is supported by VPS37D context; PMID:32424346 supports general ESCRT-I mechanism
      using a VPS37B-containing headpiece.
    additional_reference_ids:
    - PMID:32424346
    - file:human/VPS37D/VPS37D-uniprot.txt
    - file:human/VPS37D/VPS37D-notes.md
    supported_by:
    - *id010
    - *id011
    - &id016
      reference_id: PMID:32424346
      supporting_text: comprising TSG101-VPS28-VPS37B-MVB12A
- 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 biologically consistent with VPS37D ESCRT-I function, but PMID:32424346 is indirect
      for this isoform.
    action: ACCEPT
    reason: The term is supported by VPS37D ESCRT-I/MVB context; PMID:32424346 supports general ESCRT-I mechanism using a
      VPS37B-containing headpiece.
    additional_reference_ids:
    - PMID:32424346
    - PMID:15218037
    - PMID:18005716
    - file:human/VPS37D/VPS37D-uniprot.txt
    - file:human/VPS37D/VPS37D-notes.md
    supported_by:
    - *id012
    - *id013
    - *id014
    - *id015
    - *id016
- 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 biologically consistent with VPS37D ESCRT-I function, but PMID:32424346 is indirect for this
      isoform.
    action: ACCEPT
    reason: The term is supported by VPS37D ESCRT-I/MVB context; PMID:32424346 supports general ESCRT-I mechanism using a
      VPS37B-containing headpiece.
    additional_reference_ids:
    - PMID:32424346
    - PMID:15218037
    - PMID:18005716
    - file:human/VPS37D/VPS37D-uniprot.txt
    - file:human/VPS37D/VPS37D-notes.md
    supported_by:
    - *id012
    - *id013
    - *id014
    - *id015
    - *id016
- term:
    id: GO:0090148
    label: membrane fission
  evidence_type: NAS
  original_reference_id: PMID:32424346
  qualifier: involved_in
  review:
    summary: Membrane fission is a broad ESCRT-I mechanism annotation and is over-transferred for VPS37D as written.
    action: MARK_AS_OVER_ANNOTATED
    reason: The cited structural/autophagy work directly tested a VPS37B-containing headpiece and VPS28 interface mutants,
      not VPS37D; the safer VPS37D annotations are ESCRT-I complex and MVB sorting.
    proposed_replacement_terms:
    - id: GO:0000813
      label: ESCRT I complex
    - id: GO:0036258
      label: multivesicular body assembly
    additional_reference_ids:
    - PMID:32424346
    - file:human/VPS37D/VPS37D-notes.md
    supported_by:
    - *id016
    - reference_id: PMID:32424346
      supporting_text: ESCRT-I is not merely a bridging adaptor
- term:
    id: GO:0016236
    label: macroautophagy
  evidence_type: TAS
  original_reference_id: PMID:20588296
  qualifier: involved_in
  review:
    summary: Macroautophagy is over-annotated for VPS37D.
    action: MARK_AS_OVER_ANNOTATED
    reason: The accessible ESCRT autophagy evidence is broad or VPS37A-specific; there is not enough direct evidence to make
      VPS37D a phagophore-closure/autophagosome assembly factor. The autophagy-specialized ESCRT-I module is built on VPS37A's
      N-terminal ubiquitin E2 variant-like (UEVL) region; the falcon deep research notes that no equivalent VPS37A-like autophagy
      UEVL specialization has been established for VPS37D, reinforcing that macroautophagy should not be a VPS37D core annotation.
    proposed_replacement_terms:
    - id: GO:0000813
      label: ESCRT I complex
    additional_reference_ids:
    - PMID:20588296
    - PMID:31519728
    - PMID:32424346
    - file:human/VPS37D/VPS37D-notes.md
    - file:human/VPS37D/VPS37D-deep-research-falcon.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: file:human/VPS37D/VPS37D-deep-research-falcon.md
      supporting_text: no VPS37A-like autophagy UEVL specialization has been established
        in the cited studies
- 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 VPS37D cellular-component annotation.
    action: ACCEPT
    reason: VPS37D is a VPS37-family ESCRT-I subunit in TSG101-VPS28-VPS37-MVB12/UBAP variant complexes, although direct VPS37D-specific
      functional evidence is limited.
    additional_reference_ids: *id003
    supported_by: *id004
- 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 the core VPS37D/ESCRT-I endosomal cargo-sorting role.
    action: ACCEPT
    reason: VPS37D is annotated as an ESCRT-I subunit required for ubiquitin-dependent endosomal cargo sorting into multivesicular
      bodies.
    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 a supported ESCRT context but is not the core VPS37D proteostasis function.
    action: KEEP_AS_NON_CORE
    reason: Viral budding uses ESCRT-I machinery, but VPS37D-specific direct viral-budding evidence is limited and the core
      cellular role remains endosomal ESCRT-I cargo sorting.
    additional_reference_ids:
    - PMID:18005716
    - PMID:20588296
    - file:human/VPS37D/VPS37D-uniprot.txt
    - file:human/VPS37D/VPS37D-notes.md
    supported_by:
    - reference_id: PMID:18005716
      supporting_text: plays essential roles in HIV budding and endosomal protein sorting
    - reference_id: PMID:20588296
      supporting_text: viral budding, cytokinesis and, probably, autophagy
- 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 VPS37D cellular-component annotation.
    action: ACCEPT
    reason: VPS37D is a VPS37-family ESCRT-I subunit in TSG101-VPS28-VPS37-MVB12/UBAP variant complexes, although direct VPS37D-specific
      functional evidence is limited.
    additional_reference_ids: *id003
    supported_by: *id004
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:23533145
  qualifier: located_in
  review:
    summary: Extracellular exosome is a high-throughput proteomics/localization context and not a core VPS37D annotation.
    action: KEEP_AS_NON_CORE
    reason: Exosome detection is not the central VPS37D ESCRT-I endosomal sorting function.
    additional_reference_ids: &id017
    - PMID:19056867
    - PMID:23533145
    - file:human/VPS37D/VPS37D-notes.md
    supported_by: &id018
    - 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:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  qualifier: located_in
  review:
    summary: Extracellular exosome is a high-throughput proteomics/localization context and not a core VPS37D annotation.
    action: KEEP_AS_NON_CORE
    reason: Exosome detection is not the central VPS37D ESCRT-I endosomal sorting function.
    additional_reference_ids: *id017
    supported_by: *id018
- term:
    id: GO:0000813
    label: ESCRT I complex
  evidence_type: IDA
  original_reference_id: PMID:22405001
  qualifier: part_of
  review:
    summary: ESCRT-I complex membership is the central VPS37D cellular-component annotation.
    action: ACCEPT
    reason: VPS37D is a VPS37-family ESCRT-I subunit in TSG101-VPS28-VPS37-MVB12/UBAP variant complexes, although direct VPS37D-specific
      functional evidence is limited.
    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 VPS37D/ESCRT-I function.
    action: ACCEPT
    reason: VPS37D is a peripheral late-endosome/endosome-membrane ESCRT-I component in local and Reactome context.
    additional_reference_ids: *id019
    supported_by: *id020
- 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 VPS37D/ESCRT-I function.
    action: ACCEPT
    reason: VPS37D is a peripheral late-endosome/endosome-membrane ESCRT-I component in local and Reactome context.
    additional_reference_ids: *id019
    supported_by: *id020
- 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 VPS37D/ESCRT-I function.
    action: ACCEPT
    reason: VPS37D is a peripheral late-endosome/endosome-membrane ESCRT-I component in local and Reactome context.
    additional_reference_ids: *id019
    supported_by: *id020
- 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 VPS37D/ESCRT-I function.
    action: ACCEPT
    reason: VPS37D is a peripheral late-endosome/endosome-membrane ESCRT-I component in local and Reactome context.
    additional_reference_ids: *id019
    supported_by: *id020
- 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 VPS37D/ESCRT-I function.
    action: ACCEPT
    reason: VPS37D is a peripheral late-endosome/endosome-membrane ESCRT-I component in local and Reactome context.
    additional_reference_ids: *id019
    supported_by: *id020
references:
- 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:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  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:21757351
  title: UBAP1 is a component of an endosome-specific ESCRT-I complex that is essential for MVB sorting.
  findings: []
- id: PMID:22405001
  title: The UBAP1 subunit of ESCRT-I interacts with ubiquitin via a SOUBA domain.
  findings: []
- id: PMID:23533145
  title: In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine.
  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: 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:15218037
  title: The human endosomal sorting complex required for transport (ESCRT-I) and its role in HIV-1 budding.
  findings: []
- id: PMID:31519728
  title: VPS37A directs ESCRT recruitment for phagophore closure.
  findings: []
- id: file:human/VPS37D/VPS37D-uniprot.txt
  title: UniProtKB record for human VPS37D
  findings: []
- id: file:human/VPS37D/VPS37D-notes.md
  title: VPS37D review notes
  findings: []
- id: file:human/VPS37D/VPS37D-deep-research-falcon.md
  title: Falcon deep research report for VPS37D
  reference_review:
    relevance: MEDIUM
    correctness: UNVERIFIED
    review_notes: >-
      LLM-synthesized deep-research report. The VPS37D-specific claims it makes are
      appropriately hedged and consistent with the existing review: VPS37D is the
      least functionally characterized of the four human VPS37 paralogs, is a bona
      fide core ESCRT-I structural subunit, does NOT show the SH3YL1/CDIP1 selective
      interactions reported for VPS37B/C, and has no VPS37A-like autophagy UEVL
      specialization established in the cited literature; it explicitly states that
      direct VPS37D-specific mechanistic evidence remains limited. The one novel
      VPS37D-specific assertion (breast-cancer biomarker association from
      chen2025escrtmayfunction; negligible VPS37D expression in colorectal tissue
      from kolmus2021) is disease/expression context, not a molecular-function or
      core-process claim, and was not used to change any GO annotation. All other
      pathway content (autophagosome closure, cytokinetic abscission, membrane/NE
      repair, viral budding) is ESCRT-I holo-complex or VPS37A-C paralog inference
      and is NOT attributed to the VPS37D subunit. Underlying primary PMIDs were not
      independently re-verified here, hence UNVERIFIED.
core_functions:
- description: VPS37D is a VPS37-family ESCRT-I subunit that supports ESCRT-I complex organization and ubiquitin-dependent
    endosomal cargo sorting into multivesicular bodies.
  directly_involved_in:
  - id: GO:0043162
    label: ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway
  - id: GO:0036258
    label: multivesicular body assembly
  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:
  - *id005
  - *id006
  - *id007
  - *id008
  - *id009
  - *id021
  - *id012
  - *id013
  - *id014
  - *id015
  - *id010
  - *id011
proposed_new_terms: []
suggested_questions:
- question: Should VPS37D macroautophagy annotations be retired or kept non-core given that the direct phagophore-closure
    evidence is VPS37A-specific?
  experts:
  - GO autophagy editors
  - GO ESCRT curators
- question: Should generic VPS37D protein-binding annotations be replaced by ESCRT-I complex membership and specific endosomal
    sorting terms?
  experts:
  - GO molecular function editors
  - UniProt curators
suggested_experiments:
- experiment_type: VPS37 paralog phagophore closure comparison
  hypothesis: VPS37A, but not necessarily VPS37D, is the VPS37 paralog specialized for phagophore closure.
  description: Compare VPS37A, VPS37B, VPS37C, and VPS37D depletion/rescue in HT-LC3 autophagosome closure assays and parallel
    EGFR or tetherin MVB-sorting assays, using endogenous expression or matched rescue levels.
- experiment_type: VPS37D-specific ESCRT-I cargo-sorting assay
  hypothesis: VPS37D participates in a subset of ESCRT-I cargo-sorting contexts but lacks direct evidence for autophagosome
    closure.
  description: Use VPS37D-specific knockout-rescue with quantitative cargo degradation and ESCRT recruitment readouts, controlling
    for VPS37A/B/C compensation.

VPS37D

Gene Description

Existing Annotations Review

Core Functions

VPS37D is a VPS37-family ESCRT-I subunit that supports ESCRT-I complex organization and ubiquitin-dependent endosomal cargo sorting into multivesicular bodies.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Comprehensive Research Report: VPS37D (UniProt: Q86XT2), Human ESCRT-I Component

1. Gene and Protein Identity Verification

2. Key Concepts, Definitions, and Current Understanding

3. Recent Developments and Latest Research (2023-2025)

4. Current Applications, Real-World Implementations, and Disease Associations

5. Pathways and Molecular Mechanism

6. Subcellular Localization

7. Expert Opinions and Authoritative Analyses

8. Key Statistics and Data from Recent Studies

9. URLs and Publication Info for Key References

10. Summary Table for Quick Reference

References

Artifacts

Citations

📚 Additional Documentation

Notes

VPS37D review notes

Scope

Evidence synthesis

Falcon

Pn Notes

VPS37D 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

Projected GO annotations (2)

Note

📄 View Raw YAML