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