# VPS37C review notes

## Scope

VPS37C 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; for VPS37C the supported core is ESCRT-I membership, endosomal MVB cargo sorting, late-endosome/endosome-membrane localization, and secondary ESCRT-I viral budding context.

## Evidence synthesis

VPS37C is a VPS37-family ESCRT-I subunit. 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/VPS37C/VPS37C-uniprot.txt, "Component of the ESCRT-I complex"; file:human/VPS37C/VPS37C-uniprot.txt, "Required for the sorting of endocytic"]. UniProt also states that human ESCRT-I "consists of TSG101, VPS28, a VPS37 protein" and that VPS37C interacts with TSG101, VPS28, MVB12A, MVB12B, HGS, STAM2, and CEP55 [file:human/VPS37C/VPS37C-uniprot.txt, "which consists of TSG101, VPS28, a VPS37"; file:human/VPS37C/VPS37C-uniprot.txt, "Interacts with TSG101, VPS28, MVB12A and MVB12B"; file:human/VPS37C/VPS37C-uniprot.txt, "Interacts with HGS and STAM2"]. These support ESCRT-I complex and endosomal MVB sorting annotations.

The main VPS37C paper identifies it as a functional mammalian ESCRT-I component. Its abstract reports that VPS37C is a Tsg101-binding protein, that "VPS37C can form a ternary complex with Tsg101 and VPS28", that it binds Hrs, and that it is recruited to aberrant endosomes induced by Tsg101, Hrs, or dominant-negative VPS4 [PMID:15509564, "VPS37C can form a ternary complex with Tsg101 and VPS28"; PMID:15509564, "binds to another class E VPS factor, namely Hrs"; PMID:15509564, "VPS37C is recruited to aberrant endosomes"]. The same paper shows a direct viral budding context: VPS37C is recruited to the plasma membrane with HIV-1 Gag, Gag-VPS37C fusion bypasses the PTAP requirement, and engineered ESCRT-I-dependent virus budding is inhibited by VPS37C depletion [PMID:15509564, "VPS37C is recruited to the plasma membrane"; PMID:15509564, "direct fusion of VPS37C to HIV-1 Gag"; PMID:15509564, "inhibited by VPS37C depletion"]. Viral budding should be kept as a supported non-core context for this proteostasis review.

Human ESCRT-I composition papers support the shared complex architecture, but some should not be over-read as VPS37C-specific MVB evidence. PMID:18005716 says human ESCRT-I plays roles in HIV budding and endosomal 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"]. By contrast, the UBAP1 endosome-specific ESCRT-I paper says the UBAP1 complex "also contains VPS37A but not VPS37C" [PMID:21757351, "contains VPS37A but not VPS37C"]. Therefore PMID:21757351 is not used as direct support for VPS37C's core endosome-specific UBAP1 pathway, although the ESCRT-I complex term itself is supported by other references.

Structural ESCRT-I evidence supports the general mechanism but is not VPS37C-specific. PMID:32424346 determined the structure of a human ESCRT-I headpiece "comprising TSG101-VPS28-VPS37B-MVB12A" and found that ESCRT-I forms helical filaments with 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 VPS37C it should not be treated as direct evidence for autophagosome closure or a VPS37C-specific membrane-fission assay.

The `macroautophagy` rows should be treated cautiously. PMID:20588296 says ESCRT-III-mediated neck cleavage is crucial for MVBs, viral budding, cytokinesis, and "probably, autophagy", and explicitly notes that whether ESCRTs directly close autophagic necks 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 VPS37C, as the VPS37-family 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 VPS37C without additional gene-specific evidence.

VPS37C has a secondary calcium-dependent ALIX/ALG-2 interaction context. PMID:23924735 reports that VPS37B and VPS37C interact with ALG-2 more strongly than TSG101 and that ALG-2 bridges ALIX and ESCRT-I [PMID:23924735, "VPS37B and VPS37C appeared to interact with ALG-2"; PMID:23924735, "adaptor protein that bridges ALIX and ESCRT-I"]. This supports keeping calcium-dependent protein binding as non-core rather than using generic `protein binding` as a molecular function.

Generic `protein binding` rows are over-annotated. The meaningful curation targets are ESCRT-I complex membership, MVB/endosomal sorting, late-endosome/endosome-membrane localization, and supported secondary ESCRT-I interaction contexts. Extracellular exosome and nucleoplasm rows come from high-throughput localization/proteomics and should remain non-core.

## Falcon

Falcon deep research was started for VPS37C on 2026-06-02 but timed out after 600 seconds and did not produce a usable `VPS37C-deep-research-falcon.md` report. The review therefore relies on the local UniProt, GOA, cached-publication, Reactome, and PN-context evidence summarized above.