CHMP4C

CHMP4C is an ESCRT-III subunit with multifaceted roles in cytokinesis, mitotic checkpoint signaling, endosomal membrane remodeling, and receptor trafficking. During cytokinesis, CHMP4C binds Borealin to engage the chromosomal passenger complex and is phosphorylated by Aurora B, which inhibits its membrane-remodeling activity and prevents premature abscission; dephosphorylation transfers control to centralspindlin, triggering abscission completion (PMID:22422861, PMID:27784789). Independent of its ESCRT membrane-remodeling function, CHMP4C localizes to kinetochores via the NDC80 complex, recruits the RZZ checkpoint complex through direct ZW10 binding to sustain spindle assembly checkpoint signaling, and bundles microtubules through its basic N-terminal domain to stabilize kinetochore-microtubule attachments (PMID:29362225, PMID:29968190). Beyond mitosis, CHMP4C mediates fission of recycling endosomes, promotes lysosomal degradation of activated EGFR, regulates endocytic trafficking of GSK3β to modulate Wnt/β-catenin signaling, and supports midbody remnant inheritance required for primary ciliogenesis (PMID:33975940, PMID:37846580, PMID:41195682, PMID:32629610).

1. 2012 High

   Establishing that CHMP4C functions as a checkpoint factor in cytokinetic abscission resolved how cells delay membrane scission when chromatin bridges persist: CHMP4C directly engages Borealin/CPC and is phosphorylated by Aurora B to inhibit abscission.

   Evidence Reciprocal co-immunoprecipitation of CHMP4C–Borealin, phosphorylation assays, RNAi with cytokinesis phenotypic readouts in human cells

   PMID:22422861

   Open questions at the time

   • How CHMP4C phosphorylation mechanistically blocks membrane scission was not resolved
   • The downstream relay from CPC to abscission effectors was unclear
2. 2015 Medium

   Demonstrating Aurora B-dependent CHMP4C phosphorylation after ionizing radiation extended its checkpoint role beyond cytokinesis, linking CHMP4C to DNA damage-induced cell cycle regulation and radiosensitivity in cancer cells.

   Evidence Western blotting for phospho-CHMP4C, siRNA depletion with flow cytometry and γH2AX foci quantification in NSCLC cells

   PMID:26712741

   Open questions at the time

   • Mechanism by which CHMP4C influences γH2AX foci formation is unknown
   • Whether this reflects a direct DNA repair role or an indirect checkpoint effect was not distinguished
   • Single-lab finding, not independently replicated
3. 2016 High

   Reconstituting CHMP4C membrane binding and remodeling in vitro, and showing that Borealin blocks membrane association while Aurora B phosphorylation inhibits remodeling activity, provided a biochemical mechanism for abscission delay and identified centralspindlin as the relay partner for triggering abscission upon CHMP4C dephosphorylation.

   Evidence Atomic force microscopy on supported lipid bilayers, co-immunoprecipitation of CHMP4C interactome in telophase, phospho-mutant analysis

   PMID:27784789

   Open questions at the time

   • The phosphatase responsible for CHMP4C dephosphorylation was not identified
   • Whether the two spatially distinct phospho-CHMP4C pools have different functional outputs was not resolved
4. 2018 High

   Identifying CHMP4C as a kinetochore-localized promoter of spindle assembly checkpoint signaling — via direct ZW10 binding and recruitment of the RZZ/Mad1-Mad2 module — revealed a mitotic function independent of its canonical ESCRT membrane role, and its N-terminal microtubule-bundling activity explained how it stabilizes kinetochore-microtubule attachments.

   Evidence RNAi with mitotic checkpoint assays, co-immunoprecipitation of CHMP4C–ZW10 and CHMP4C–Hec1/Nuf2, in vitro microtubule binding/bundling, constitutive kinetochore-tethering constructs

   PMID:29362225 PMID:29968190

   Open questions at the time

   • How CHMP4C is regulated at kinetochores (e.g., whether Aurora B phosphorylation modulates its kinetochore functions) is unknown
   • Structural basis for CHMP4C–ZW10 interaction was not determined
   • Whether the kinetochore and cytokinesis pools of CHMP4C are sequentially regulated in mitosis remains unclear
5. 2020 Medium

   Linking CHMP4C to midbody remnant inheritance and primary ciliogenesis showed that its abscission-related membrane function has downstream consequences for organelle biogenesis in epithelial cells.

   Evidence Correlative light and ultra-high-resolution scanning electron microscopy, siRNA depletion with ciliation readout

   PMID:32629610

   Open questions at the time

   • The specific membrane topology CHMP4C maintains at the midbody stalk is not defined
   • Whether this ciliogenesis defect is solely due to MBR loss or involves additional CHMP4C functions was not tested
   • Single study without independent replication
6. 2021 Medium

   Demonstrating that CHMP4C — uniquely among CHMP4 paralogues — is required for recycling endosome fission established a non-mitotic, paralogue-specific membrane scission role in the endosomal system.

   Evidence siRNA depletion screen, ultrastructural EM of tubulated recycling endosomes, confocal co-localization with transferrin receptor

   PMID:33975940

   Open questions at the time

   • How CHMP4C is specifically recruited to recycling endosomes is unknown
   • Whether VPS4 is required for this fission event was not tested
   • Single study; independent confirmation is lacking
7. 2023 Medium

   Showing that CHMP4C directly interacts with EGFR and promotes its lysosomal degradation provided a molecular link between ESCRT-III sorting and receptor downregulation, with in vivo relevance demonstrated by exacerbated cardiac hypertrophy in CHMP4C knockout mice rescued by EGFR inhibition.

   Evidence Co-immunoprecipitation of CHMP4C–EGFR, cardiac-specific overexpression and global knockout mouse models, EGFR inhibitor rescue

   PMID:37846580

   Open questions at the time

   • Whether CHMP4C sorts other RTKs beyond EGFR is unknown
   • The mechanism distinguishing CHMP4C from other ESCRT-III subunits in EGFR degradation is not defined
   • Single study
8. 2025 Medium

   Two studies expanded CHMP4C's non-mitotic repertoire: one showed CHMP4C regulates endocytic trafficking of GSK3β to control Wnt/β-catenin signaling and angiogenesis, and another revealed CHMP4C–YBX1-mediated m5C modification of caspase-8 mRNA to suppress necroptosis, with additional exocytic secretion of phospho-MLKL via extracellular vesicles.

   Evidence siRNA/KO with RNA-Seq and EM-based trafficking analysis plus GSK3β inhibitor rescue in endothelial cells and hind-limb ischemia model; RIP, MeRIP-qPCR, Co-IP of CHMP4C–YBX1, and EV isolation in pancreatic cancer cells with in vivo validation

   PMID:39870301 PMID:41195682

   Open questions at the time

   • Whether CHMP4C's role in GSK3β trafficking involves its recycling endosome fission activity is not established
   • The CHMP4C–YBX1 interaction and m5C regulatory axis have not been independently replicated
   • How CHMP4C selectively packages phospho-MLKL into EVs is mechanistically undefined

• Major unresolved questions include how CHMP4C is differentially recruited to its distinct functional sites (kinetochores, midbody, recycling endosomes, late endosomes), what phosphatase reverses Aurora B phosphorylation to trigger abscission, whether CHMP4C's kinetochore and cytokinesis functions are coordinated during mitotic progression, and the structural basis for its paralogue-specific activities.
• No structural model of CHMP4C–ZW10 or CHMP4C–Borealin complexes exists
• Identity of CHMP4C phosphatase unknown
• Basis for paralogue specificity (CHMP4C vs. CHMP4A/B) at recycling endosomes not determined