CHMP6

CHMP6 (VPS20) is an N-myristoylated ESCRT-III subunit that bridges ESCRT-II to the downstream ESCRT-III polymer to drive membrane scission (PMID:15511219, PMID:21835927). It binds directly to the ESCRT-II subunit EAP20/Vps25 through its N-terminal basic half and engages the ESCRT-III subunit CHMP4b/Snf7, and it is additionally recruited via a conserved surface on the Vps28 C-terminal domain of ESCRT-I (PMID:15511219, PMID:16749904). Unlike autoinhibited ESCRT-III subunits, CHMP6 adopts an open, extended conformation that permits constitutive ESCRT-II engagement independent of membranes (PMID:25588614). On highly curved membranes the ESCRT-II–CHMP6 assembly nucleates flexible Snf7/Vps32 filaments that remodel the bilayer, the molecular basis of intralumenal vesicle formation in multivesicular body sorting (PMID:21835927, PMID:14583093); consistent with this, CHMP6 localizes to MVB membranes and is required for endosomal cargo sorting, including the downregulation of transferrin receptor and EGF (PMID:15511219). The same ESCRT-II–CHMP6 nucleation module assembles into ordered structures at the cytokinetic intercellular bridge, where a CHMP6 N-terminal fragment acts as a dominant-negative that blocks abscission in an ESCRT-II-binding-dependent manner (PMID:25232011). CHMP6 activity is regulated by accessory factors: it presents a MIM1-like motif bound by the deubiquitinase Doa4, and Bro1 binding relieves CHMP6-mediated antagonism of the Doa4–Snf7 interaction (PMID:23444383, PMID:34908216). Beyond canonical scission, CHMP6 binds GTP-loaded, ubiquitylated H-Ras and N-Ras to promote recycling of Ras and EGFR to the plasma membrane (PMID:22231449), and its myristoylated N-terminal peptide is sufficient to enhance small extracellular vesicle production and cargo loading (PMID:35188876).

1. 2004 Medium

   Establishing whether the human VPS20 ortholog behaved as a bona fide ESCRT-III subunit was the first step in placing CHMP6 in the endosomal machinery.

   Evidence Immunofluorescence and co-expression with hSnf7-1 in mammalian cells

   PMID:14583093

   Open questions at the time

   • No direct binding assay for human Vps20 in this study
   • Functional interaction inferred from co-expression phenotype only
2. 2005 High

   Defining CHMP6's molecular connections answered how ESCRT-II is physically linked to ESCRT-III and showed CHMP6 is lipid-modified, anchoring it as the membrane-proximal nucleator.

   Evidence Metabolic [3H]myristate labelling, co-IP and recombinant pull-down with domain mapping, and MVB localization/cargo-sorting assays in HEK-293 and HeLa cells

   PMID:15511219

   Open questions at the time

   • Cargo-sorting readouts rely on overexpression
   • Did not resolve filament-nucleation mechanism
3. 2006 High

   Identifying a second upstream contact resolved how the ESCRT-I subunit Vps28 helps recruit CHMP6/ESCRT-III, structurally defining the recruitment surface.

   Evidence Crystal structure of Vps28-CTD with mutagenesis, in vitro binding, and EIAV Gag late-domain rescue

   PMID:16749904

   Open questions at the time

   • Relative contribution of Vps28 versus ESCRT-II to recruitment in cells not quantified
4. 2011 High

   Reconstitution answered how ESCRT-II and CHMP6 generate membrane deformation, showing they nucleate curvature-dependent Snf7 filaments.

   Evidence Liposome co-flotation, fluorescence interaction assays, and high-resolution AFM with purified recombinant proteins

   PMID:21835927

   Open questions at the time

   • Single-lab in vitro system
   • How filament dynamics couple to scission not directly demonstrated
5. 2012 Medium

   A screen revealed a non-canonical role: CHMP6 directly engages GTP-loaded, ubiquitylated H-/N-Ras to drive Ras and EGFR recycling, linking ESCRT-III to growth factor signaling feedback.

   Evidence cDNA library screen, direct binding, cell fractionation, FRAP, and knockdown with EGFR-recycling and transformation assays

   PMID:22231449

   Open questions at the time

   • Single lab
   • Mechanism connecting recycling to canonical scission activity unresolved
6. 2013 High

   Mapping the Doa4 contact explained how deubiquitination is coupled to ESCRT-III, showing CHMP6 carries a MIM1-like motif bound by the Doa4 MIT domain.

   Evidence In vitro direct binding, yeast epistasis/rescue in bro1Δ, and mutagenesis

   PMID:23444383

   Open questions at the time

   • Conservation of this regulatory motif in human CHMP6 not tested here
7. 2014 High

   Imaging and structure-function dissection established that the ESCRT-II–CHMP6 module operates at the cytokinetic bridge and that its N-terminal ESCRT-II-binding activity is essential for abscission.

   Evidence High-resolution imaging of endogenous proteins, dominant-negative truncation, structure-function mutagenesis, and cell death assays

   PMID:25232011

   Open questions at the time

   • Distinct contributions of the first 10 residues versus ESCRT-II binding not fully separated mechanistically
8. 2015 Medium

   Conformational analysis answered why CHMP6 can constitutively bind ESCRT-II, showing it is an open, extended subunit rather than autoinhibited.

   Evidence In vitro binding with recombinant proteins, conformational analysis, and extract co-precipitation in C. elegans VPS-20

   PMID:25588614

   Open questions at the time

   • Single lab, ortholog system
   • No high-resolution structure of the open state
9. 2022 High

   Two findings extended CHMP6 regulation and function: Bro1 relieves CHMP6 antagonism of Doa4–Snf7 binding, and the CHMP6 myristoylated N-terminus is sufficient to promote extracellular vesicle biogenesis and cargo loading.

   Evidence In vitro binding plus yeast epistasis/co-IP (Bro1); NTA, TEM, luciferase cargo assays, WB, and editing reporter in Lenti-X 293T cells (Myr-CHMP6 EVs)

   PMID:34908216 PMID:35188876

   Open questions at the time

   • Additional N-terminal sequences required for EV packaging not identified
   • Mechanistic link between Bro1 regulation and EV biogenesis not established
10. 2025 Low

    A disease-context study linked CHMP6 to CEP55 and ferroptosis suppression in triple-negative breast cancer.

    Evidence Co-IP, Western blot, ferroptosis assays, and xenograft model

    PMID:40925844

    Open questions at the time

    • Single co-IP without reciprocal validation
    • No mechanism for how CEP55 promotes CHMP6 expression
    • Connection to ESCRT scission function not established

• How CHMP6's canonical ESCRT-III nucleation role mechanistically integrates with its non-canonical Ras/EGFR recycling and tumor-associated ferroptosis functions remains unresolved.
• No structure of the human ESCRT-II–CHMP6 complex
• Whether recycling and scission activities use the same or distinct interaction surfaces unknown
• In vivo disease relevance of ferroptosis link untested beyond single study