CHMP4C

CHMP4C is an ESCRT-III subunit that times the final membrane-scission step of cytokinesis through the Aurora B-dependent abscission checkpoint, coupling abscission to faithful chromosome segregation (PMID:22422861). It interacts with the chromosomal passenger complex via Borealin, and Aurora B phosphorylation of CHMP4C interferes with its membrane-remodeling activity while leaving its assembly into spiral filaments at the abscission site intact; gradual dephosphorylation hands CHMP4C from the CPC to centralspindlin, which preferentially binds the unphosphorylated form to license abscission (PMID:22422861, PMID:27784789). Beyond cytokinesis, CHMP4C carries out an ESCRT-independent role at prometaphase kinetochores, binding ZW10 directly and associating with the NDC80 components Hec1 and Nuf2 to promote RZZ and Mad1-Mad2 recruitment and the spindle assembly checkpoint, and it directly bundles microtubules through its basic N-terminal region (residues 1–77) to support cold-stable kinetochore fibers and chromosome alignment (PMID:29362225, PMID:29968190). CHMP4C also acts in membrane-trafficking contexts: it is required for fission of transferrin receptor-positive recycling endosome tubules, an activity not shared by its paralogs CHMP4A/B, and for midbody remnant inheritance and ciliation in epithelial cells (PMID:32629610, PMID:33975940). In differentiated tissues it directs endocytic/lysosomal fate of signaling receptors—promoting lysosomal degradation of activated EGFR to limit cardiac hypertrophy and modulating GSK3β endocytic trafficking to sustain Wnt/β-catenin signaling and angiogenesis (PMID:37846580, PMID:41195682). In pancreatic cancer cells it suppresses necroptosis by partnering with YBX1 to deposit m5C on caspase-8 mRNA and by promoting exocytosis of phospho-MLKL (PMID:39870301).

1. 2012 High

   Established CHMP4C as the ESCRT-III subunit that enforces an abscission checkpoint, answering how cytokinesis is delayed when chromatin remains in the cleavage plane.

   Evidence Co-IP with Borealin/CPC, loss-of-function showing premature abscission and DNA damage, and spatiotemporal localization during cytokinesis

   PMID:22422861

   Open questions at the time

   • Did not resolve the in vitro biochemical consequence of Aurora B phosphorylation
   • Phosphosite-to-mechanism link not mapped structurally
2. 2016 High

   Defined the biochemical logic of the checkpoint: phosphorylation gates membrane remodeling (not filament assembly), and a CPC-to-centralspindlin relay reads CHMP4C phosphostate to time activation.

   Evidence Atomic force microscopy of membrane binding/remodeling in vitro, telophase interactome by MS/Co-IP, centralspindlin Co-IP, and phospho-mutant analysis

   PMID:27784789

   Open questions at the time

   • Structural basis of phospho-dependent remodeling inhibition not solved
   • How dephosphorylation kinetics are controlled in vivo unclear
3. 2018 High

   Revealed an ESCRT-independent kinetochore function: CHMP4C binds ZW10 and promotes RZZ/Mad1-Mad2 recruitment to drive the spindle assembly checkpoint, expanding its role beyond membrane scission.

   Evidence siRNA depletion, ZW10 Co-IP, domain mapping, constitutive kinetochore targeting, and nocodazole checkpoint assay

   PMID:29362225

   Open questions at the time

   • How CHMP4C is recruited to kinetochores not fully defined here
   • Relationship between kinetochore pool and cytokinetic pool unaddressed
4. 2018 High

   Connected CHMP4C to the NDC80 complex and identified a direct microtubule-bundling activity in its N-terminal basic region, explaining its contribution to kinetochore-microtubule stability and chromosome alignment.

   Evidence Co-IP with Hec1/Nuf2, in vitro microtubule binding/bundling assay, N-terminal domain mutagenesis, and depletion-rescue

   PMID:29968190

   Open questions at the time

   • Whether microtubule bundling is regulated by Aurora B phosphorylation untested
   • Stoichiometry of CHMP4C within the kinetochore not defined
5. 2015 Medium

   Showed the Aurora B–CHMP4C axis confers radiation resistance independent of p53, linking the checkpoint role to cancer cell survival.

   Evidence siRNA depletion, phospho Western blot, colony formation, cell-cycle flow cytometry, γH2AX/53BP1 foci, and Aurora B inhibitor in NSCLC cells

   PMID:26712741

   Open questions at the time

   • No direct phosphosite mapping or mutagenesis
   • Single lung-cancer model; generality untested
6. 2020 Medium

   Demonstrated CHMP4C is required for midbody remnant inheritance and ciliation, tying its membrane activity to a structural connection at the apical surface.

   Evidence Correlative light and ultra-high-resolution scanning EM, siRNA depletion, and ciliation assay

   PMID:32629610

   Open questions at the time

   • Molecular partners maintaining the membranous stalk not identified
   • Single epithelial system
7. 2021 Medium

   Identified a paralog-specific role for CHMP4C in fission of recycling endosome tubules, distinguishing it functionally from CHMP4A/CHMP4B.

   Evidence siRNA screen, EM and confocal microscopy of tubulation/fission defect, HSV1 envelopment assay, and exogenous localization to recycling endosomes

   PMID:33975940

   Open questions at the time

   • No in vitro reconstitution of the fission reaction
   • Adaptors targeting CHMP4C to recycling endosomes unknown
8. 2023 Medium

   Placed CHMP4C in receptor-degradation control by showing it drives lysosomal degradation of activated EGFR to restrain cardiac hypertrophy.

   Evidence Co-IP, colocalization imaging, CHMP4C KO and cardiac-specific overexpression mice with transverse aortic constriction, and EGFR inhibitor rescue

   PMID:37846580

   Open questions at the time

   • No in vitro reconstitution of EGFR sorting
   • Whether ESCRT-III machinery is engaged here not dissected
9. 2025 Medium

   Extended the trafficking role to GSK3β, showing CHMP4C-dependent endocytic trafficking restrains GSK3β activity to sustain Wnt/β-catenin signaling and angiogenesis.

   Evidence CHMP4C KO mice (hind-limb ischemia), siRNA knockdown, RNA-Seq, EM/IHC colocalization, and GSK3β inhibitor rescue

   PMID:41195682

   Open questions at the time

   • Direct CHMP4C–GSK3β physical interaction not established
   • Mechanism of GSK3β trafficking step unresolved
10. 2025 Medium

    Uncovered an RNA-modification role: CHMP4C partners with YBX1 to deposit m5C on caspase-8 mRNA and promotes phospho-MLKL exocytosis, suppressing necroptosis in pancreatic cancer.

    Evidence RNA-IP, MeRIP-qPCR, YBX1 Co-IP, differential ultracentrifugation for EVs, and in vitro/in vivo functional assays

    PMID:39870301

    Open questions at the time

    • Whether CHMP4C has intrinsic RNA-binding/m5C activity versus a scaffolding role unclear
    • Single cancer model; replication limited

• How a single ESCRT-III subunit coordinates its membrane-scission, microtubule-bundling, receptor-sorting, and RNA-modification roles—and which interactions partition it among these functions—remains unresolved.
• No unifying structural model links the diverse activities
• Regulation switching CHMP4C between kinetochore, endosomal, and abscission pools not defined