VPS37C

VPS37C is a core subunit of mammalian ESCRT-I that assembles with TSG101 and VPS28 into a ternary complex and also binds the class E VPS factor HRS, defining a complex isoform distinct from the endosome-specific UBAP1/VPS37A-containing ESCRT-I (PMID:15509564, PMID:21757351). In this capacity it is required for PTAP-dependent (ESCRT-I-dependent) retroviral budding but dispensable for PPPY-dependent budding, as shown by depletion phenotypes and rescue when VPS37C is fused directly to a PTAP-deleted HIV-1 Gag (PMID:15509564, PMID:18723511). This budding function is negatively regulated by TBK1, which directly binds and phosphorylates VPS37C to attenuate PTAP-dependent release independently of type I interferon signaling (PMID:21270402). VPS37C-containing ESCRT-I is bridged to the accessory factor ALIX through the Ca2+-dependent adaptor ALG-2, forming an ESCRT-I/ALIX/ALG-2 ternary complex, and this same ALG-2 adaptor links VPS37C-containing ESCRT-I to CDIP1 to promote caspase-3/7-mediated cell death (PMID:23924735, PMID:33503978). VPS37C contributes non-redundantly to overall ESCRT-I structural integrity: combined depletion of VPS37A/B/C destabilizes the complex and triggers p21/CDKN1A-mediated proliferation arrest and NF-κB-driven sterile inflammatory responses (PMID:33419951). Beyond its ESCRT role, VPS37C stabilizes the EKLF/KLF1 transcription factor by blocking its K48-linked polyubiquitination and proteasomal degradation, thereby promoting erythroid differentiation (PMID:37307706).

1. 2004 High

   Established VPS37C as a bona fide ESCRT-I subunit and connected it functionally to ESCRT-dependent membrane budding, answering whether it is a structural component versus a peripheral factor.

   Evidence Yeast two-hybrid, Co-IP forming a TSG101/VPS28 ternary complex, localization to aberrant endosomes, siRNA depletion blocking PTAP-dependent budding, and Gag-VPS37C fusion rescue

   PMID:15509564

   Open questions at the time

   • Stoichiometry and structural organization within ESCRT-I not resolved
   • Endogenous cargo sorting role distinct from viral budding not defined
2. 2008 High

   Clarified that PTAP- versus PPPY-dependent viral budding pathways have divergent ESCRT-I requirements, with VPS37C specifically needed for HIV-1 but not ASV release.

   Evidence siRNA depletion of endogenous VPS37C with viral particle release assays across two retroviral systems plus fusion rescue

   PMID:18723511

   Open questions at the time

   • Molecular basis for late-domain selectivity not detailed
   • Role of other VPS37 isoforms in the same assays not contrasted
3. 2011 High

   Demonstrated that VPS37C defines a distinct ESCRT-I isoform separate from the UBAP1/VPS37A endosomal complex, addressing whether VPS37 paralogs are interchangeable.

   Evidence Reciprocal Co-IP showing UBAP1 associates with VPS37A but not VPS37C, with EGFR-degradation endosomal sorting assays

   PMID:21757351

   Open questions at the time

   • Cellular contexts that select one isoform over another unknown
   • Functional consequences of isoform identity for distinct cargoes not mapped
4. 2011 Medium

   Identified TBK1 as a direct regulator of VPS37C, establishing a kinase-mediated brake on ESCRT-dependent budding outside of interferon signaling.

   Evidence Co-IP of TBK1–VPS37C, shRNA knockdown, kinase-dead K38A mutant, and budding assays in TBK1-knockout MEFs

   PMID:21270402

   Open questions at the time

   • In vitro kinase assay confirming direct phosphorylation not described
   • Phosphorylation site(s) on VPS37C not mapped
5. 2013 Medium

   Defined how VPS37C-containing ESCRT-I couples to the ALIX branch, showing ALG-2 acts as a Ca2+-dependent bridge into an ESCRT-I/ALIX/ALG-2 ternary complex.

   Evidence Far-Western with ALG-2 probe, pulldown of recombinant ESCRT-I complexes, and in vitro binding with purified proteins

   PMID:23924735

   Open questions at the time

   • Physiological process requiring this Ca2+-dependent bridge not established
   • Single-lab in vitro reconstitution
6. 2021 Medium

   Linked VPS37C-containing ESCRT-I to programmed cell death by showing isoform-selective association with CDIP1 via ALG-2 that potentiates caspase activation.

   Evidence Co-IP of GFP-CDIP1 with ESCRT-I isoforms and caspase-3/7 cell death assays in HEK293 cells

   PMID:33503978

   Open questions at the time

   • Endogenous (non-overexpression) relevance not shown
   • Mechanism connecting ESCRT-I/CDIP1 to caspase activation unresolved
7. 2021 Medium

   Showed VPS37C contributes non-redundantly to ESCRT-I integrity, with combinatorial loss triggering cell-cycle arrest and sterile inflammation.

   Evidence Individual and combined siRNA knockdown, transcriptomics, ESCRT-I stability blots, NF-κB reporter and p21 readouts

   PMID:33419951

   Open questions at the time

   • Direct trigger linking ESCRT-I destabilization to NF-κB not identified
   • Single-knockdown VPS37C phenotype relatively mild
8. 2023 Medium

   Revealed a non-ESCRT function in which VPS37C stabilizes the EKLF transcription factor to drive erythroid differentiation, expanding its role beyond membrane trafficking.

   Evidence Co-IP, K48-linkage-specific ubiquitination assay, overexpression/knockdown in MEL cells with induced differentiation, and EKLF re-expression rescue

   PMID:37307706

   Open questions at the time

   • Whether stabilization requires ESCRT-I assembly or is ESCRT-independent unclear
   • Direct biochemical mechanism preventing K48 ubiquitination not defined
9. 2024 Low

   Identified VPS37C as an intracellular binding target of hydroxychloroquine, raising a potential pharmacological link.

   Evidence POST-IT non-diffusive proximity tagging in live cells

   PMID:39728918

   Open questions at the time

   • Functional consequence of the hydroxychloroquine–VPS37C interaction not characterized
   • Binding not orthogonally validated

• How VPS37C isoform-specific ESCRT-I complexes are selected for distinct cargoes, and how the ESCRT and EKLF-stabilizing roles are integrated, remains unresolved.
• No structural model of VPS37C within ESCRT-I
• Endogenous physiological cargoes and tissue-specific roles undefined
• Mechanistic link between ESCRT membership and transcription-factor stabilization unknown