Affinage

CHMP7

Charged multivesicular body protein 7 · UniProt Q8WUX9

Length
453 aa
Mass
50.9 kDa
Annotated
2026-04-28
16 papers in source corpus 13 papers cited in narrative 13 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CHMP7 is an ESCRT-II/ESCRT-III hybrid protein that functions as a critical nucleator of ESCRT-III-dependent membrane remodeling at the nuclear envelope, with additional roles in endosomal sorting, ER–mitochondria contact site tethering, and telomere integrity. Its N-terminal tandem Winged-Helix domains mediate ER membrane binding and nuclear envelope recruitment, while its C-terminal SNF7-like domain interacts directly with CHMP4B and with the inner nuclear membrane adaptor LEM2, enabling spatially restricted assembly of downstream ESCRT-III polymers (CHMP2A, IST1/CHMP8) to seal nuclear envelope holes during mitotic exit and interphase rupture repair (PMID:27618263, PMID:28242692). CDK1-mediated phosphorylation of CHMP7 at Ser3 and Ser441 suppresses LEM2 interaction during mitosis, and dephosphorylation at telophase licenses CHMP7 assembly specifically at the reforming nuclear envelope (PMID:34286694). In motor neurons, aberrant nuclear accumulation of CHMP7—promoted by SUN1 and CHMP2B and opposed by the SmD1/SMN splicing complex—overactivates nuclear pore complex surveillance, causing nucleoporin loss and TDP-43 dysfunction relevant to ALS pathogenesis (PMID:34321318, PMID:39709457, PMID:39486415).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2006 Medium

    Identifying CHMP7 as an ESCRT-III-related protein that directly binds CHMP4B established it as a new component of the endosomal sorting machinery, raising the question of its specific cellular function beyond canonical ESCRT-III members.

    Evidence Pull-down assays in HEK-293T cells with domain mapping; VLP release and ubiquitinated cargo accumulation assays

    PMID:16856878

    Open questions at the time
    • No reciprocal co-IP or endogenous interaction validation
    • Endosomal sorting role based on overexpression phenotypes only
    • Physiological substrates or cargo not identified
  2. 2016 High

    Demonstrating that the N-terminal Winged-Helix domains constitute a membrane-binding module required for ER localization and NE recruitment redirected the field from viewing CHMP7 as a canonical endosomal ESCRT factor to understanding it as a nuclear envelope ESCRT adaptor.

    Evidence Homology modeling, membrane-binding assays, point mutagenesis with live-cell imaging of NE reformation

    PMID:27618263

    Open questions at the time
    • Structural basis of Winged-Helix membrane binding not resolved at atomic level
    • How CHMP7 transitions from ER-resident to NE-enriched pool was unclear
  3. 2017 High

    Identifying LEM2 as the inner nuclear membrane adaptor that directly recruits CHMP7 via its C-terminal domain established the minimal receptor–effector pair for site-specific ESCRT-III nucleation at the nuclear envelope, conserved from yeast to human.

    Evidence In vitro binding of purified proteins, RNAi knockdown in human cells, S. pombe genetic epistasis (lem2/cmp7 suppression of vps4Δ)

    PMID:28242692

    Open questions at the time
    • Stoichiometry and structural basis of LEM2–CHMP7 complex unknown
    • Whether additional NE adaptors exist in metazoans was unresolved
  4. 2020 Medium

    Genetic cooperation between CHMP7/LEM2 and the CNEP-1/lipin lipid synthesis pathway in C. elegans revealed that ESCRT-III sealing of NE holes operates in parallel with regulated membrane lipid supply, broadening the model of NE closure beyond a purely ESCRT-dependent mechanism.

    Evidence C. elegans double-mutant genetics, 3D electron microscopy, NE permeability assays

    PMID:32271860

    Open questions at the time
    • Whether the lipid synthesis pathway similarly cooperates with CHMP7 in mammalian cells was untested
    • Mechanistic basis of ER membrane restriction at NE holes not defined
  5. 2021 High

    Discovery that CDK1 phosphorylates CHMP7 at Ser3/Ser441 to suppress LEM2 binding during mitosis, with dephosphorylation licensing assembly at telophase, answered how CHMP7 activation is temporally coordinated with cell cycle exit to prevent premature ESCRT-III polymerization.

    Evidence Phospho-site mutagenesis, co-IP of phosphomimetic/alanine mutants with LEM2, live-cell imaging of mitotic exit

    PMID:34286694

    Open questions at the time
    • Identity of the phosphatase(s) responsible for CHMP7 dephosphorylation at telophase unknown
    • Whether additional post-translational modifications regulate CHMP7 activity
  6. 2021 High

    Showing that aberrant nuclear accumulation of CHMP7 is sufficient to trigger NPC injury, nucleoporin loss, and TDP-43 dysfunction in ALS neurons—and that CHMP7 knockdown rescues these phenotypes—established CHMP7 as a central effector linking ESCRT-III dysregulation to neurodegeneration.

    Evidence iPSC-derived spinal motor neurons, ASO knockdown and lentiviral nuclear export blockade of CHMP7, postmortem ALS tissue validation

    PMID:34321318

    Open questions at the time
    • What initially triggers CHMP7 nuclear accumulation in disease neurons was unknown
    • Whether CHMP7-mediated NPC injury is reversible in vivo
  7. 2022 Medium

    Localization of CHMP7 to ER three-way junctions and ER–mitochondria contact sites, with a role in mitochondrial tethering and division independent of canonical ESCRT activity, expanded CHMP7's functional repertoire beyond NE sealing.

    Evidence Super-resolution microscopy, domain deletion analysis, CHMP7 depletion with mitochondrial division readout

    PMID:35962186

    Open questions at the time
    • ESCRT-independent mechanism of ER–mitochondria tethering not molecularly defined
    • Whether this function is physiologically separable from NE roles in vivo
  8. 2023 Medium

    Demonstrating that BAF-LEM and LEM2-CHMP7 represent distinct redundant NE closure mechanisms in C. elegans resolved how embryos tolerate loss of either pathway alone but require at least one for viability.

    Evidence C. elegans genetics with BAF-1, LEM-2, EMR-1 combinatorial mutants; domain-specific rescue; NE permeability imaging

    PMID:37795681

    Open questions at the time
    • Whether redundancy with BAF-LEM exists in mammalian systems not tested
    • Nucleoplasmic CHMP7 pool function not molecularly characterized
  9. 2024 Medium

    Identification of SUN1 and CHMP2B as upstream factors that promote pathological CHMP7 nuclear accumulation in sALS neurons provided the missing mechanistic link between NPC barrier defects and CHMP7-driven neurodegeneration.

    Evidence Co-IP of SUN1–CHMP7 and CHMP2B epistasis in iPSC-derived sALS neurons; knockdown rescue of NPC injury and TDP-43 dysfunction

    PMID:37639327 PMID:39709457

    Open questions at the time
    • Direct versus indirect nature of SUN1–CHMP7 interaction not resolved with purified proteins
    • Whether CHMP2B activates CHMP7 through conformational change or relocalization is unknown
  10. 2024 Medium

    Discovery that SmD1/SMN complex integrity controls CHMP7 cytoplasmic retention, with SmD1 loss promoting nuclear CHMP7 accumulation, revealed an unexpected RNA-splicing-dependent checkpoint on ESCRT-III nuclear surveillance.

    Evidence IP-MS, eCLIP, CRaft-ID screen, SmD1 overexpression rescue in ALS iPSC-MNs

    PMID:39486415

    Open questions at the time
    • Whether CHMP7 RNA-binding is direct or bridged through SmD1 not fully resolved
    • Mechanism linking splicing defects to CHMP7 relocalization remains indirect
  11. 2026 Medium

    Placing CHMP7 in a genetic pathway with CHMP4B and AKTIP/Ft1 for telomere integrity, and with SATB2-LEMD2 for activity-dependent transcription in neurons, extended CHMP7's nuclear roles to genome maintenance and gene regulation beyond NE sealing.

    Evidence siRNA double-knockdown epistasis with telomere integrity assays; shRNA knockdown in cortical neurons with RNA-seq and immunofluorescence

    PMID:41677621 PMID:41744617

    Open questions at the time
    • Telomere role based on knockdown phenotypes without direct mechanistic target identified
    • Activity-dependent transcription phenotype lacks direct molecular mechanism (Low confidence)
    • Whether telomere and transcription phenotypes are secondary to NE integrity defects not excluded

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the atomic structure of the CHMP7–LEM2 complex, the identity of phosphatase(s) that activate CHMP7 at telophase, whether CHMP7's ER–mitochondria tethering and telomere maintenance roles are mechanistically independent of NE sealing, and whether therapeutic targeting of CHMP7 nuclear accumulation can ameliorate neurodegeneration in vivo.
  • No high-resolution structure of full-length CHMP7 or CHMP7–LEM2 complex
  • Phosphatase identity unknown
  • In vivo therapeutic validation absent

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3 GO:0008289 lipid binding 2
Localization
GO:0005635 nuclear envelope 4 GO:0005634 nucleus 3 GO:0005783 endoplasmic reticulum 2 GO:0005739 mitochondrion 1
Pathway
R-HSA-1852241 Organelle biogenesis and maintenance 5 R-HSA-1643685 Disease 3 R-HSA-1640170 Cell Cycle 1
Partners
AKTIPCHMP2ACHMP2BCHMP4BIST1LEM2SNRNPD1SUN1
Complex memberships
ESCRT-III

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 CHMP7 is a novel ESCRT-III-related protein that directly interacts with CHMP4b via its C-terminal SNF7 domain, as shown by pull-down assays. Overexpression of CHMP7 causes accumulation of ubiquitinated proteins and endocytosed EGF, and inhibits MLV Gag virus-like particle release, establishing a role in the endosomal sorting pathway. Pull-down assay (Strep-tagged CHMP7 with GFP-CHMP4b in HEK-293T lysates), confocal fluorescence microscopy, dominant-negative VPS4B co-localization, virus-like particle release assay The Biochemical journal Medium 16856878
2016 The N-terminal tandem Winged-Helix domains of CHMP7 constitute a novel membrane-binding module that mediates ER localization and is required for CHMP7 recruitment to the reforming nuclear envelope during mitotic exit. Point mutations disrupting membrane binding prevent ER localization, NE enrichment, downstream ESCRT-III assembly, and proper nucleo-cytoplasmic compartmentalization. Homology modeling, structure-function analysis with point mutations, live-cell imaging, membrane-binding assays, nuclear envelope reformation assay Current biology : CB High 27618263
2017 LEM2 (inner nuclear membrane LEM-domain protein) directly binds the C-terminal domain of CHMP7 in vitro and acts as a conserved nuclear-site-specific adaptor that recruits CHMP7 and downstream ESCRT-III factors (CHMP2A, IST1/CHMP8) to the nuclear envelope during NE reformation. Genetic epistasis in S. pombe showed lem2 and cmp7 loss-of-function suppresses vps4-deletion nuclear morphology defects, placing them upstream in the same pathway. In vitro binding assay (purified proteins), co-enrichment by fluorescence microscopy during NE reformation, RNAi knockdown of LEM2 with ESCRT recruitment readout, S. pombe genetic epistasis (suppressor screen) Proceedings of the National Academy of Sciences of the United States of America High 28242692
2020 In C. elegans, LEM-2 and CHMP-7 cooperate with regulated lipid synthesis (via CNEP-1/CTDNEP1 and lipin) to close nuclear envelope holes; ESCRT-III components accumulate at NE openings and their NE adaptors restrict ER membrane invasion into holes, with genetic interaction between NE ESCRT adaptors and CNEP-1 demonstrating that both pathways jointly ensure NE closure. C. elegans genetics (double mutants), 3D electron microscopy, fluorescence imaging of NE permeability barrier The Journal of cell biology Medium 32271860
2021 CDK1 phosphorylates CHMP7 at Ser3 and Ser441 upon mitotic entry, reducing its interaction with LEM2 and suppressing CHMP7 assembly during M-phase. Spatiotemporal dephosphorylation of CHMP7 during telophase licenses CHMP7-LEM2 interaction specifically at the NE but not on the peripheral ER, coordinating ESCRT-III-dependent nuclear envelope reformation with cell cycle progression. Live-cell imaging, protein biochemistry (co-immunoprecipitation, phospho-mapping), CDK1 phosphorylation site mutagenesis (Ser3/Ser441), mitotic exit imaging assays eLife High 34286694
2021 Aberrant nuclear accumulation of CHMP7 in ALS neurons initiates nuclear pore complex injury, including reduction of specific nucleoporins, Ran GTPase mislocalization, and TDP-43 dysfunction. Inhibiting CHMP7 nuclear export was sufficient to trigger NPC damage, while CHMP7 knockdown alleviated Nup alterations, TDP-43 mRNA defects, and glutamate-induced neuronal death in iPSC-derived spinal neurons. iPSC-derived neuron model, antisense oligonucleotide knockdown of CHMP7, lentiviral nuclear export inhibition, postmortem tissue immunofluorescence, TDP-43 mRNA expression assays Science translational medicine High 34321318
2022 CHMP7 localizes to ER three-way junctions and ER-mitochondria membrane contact sites (MCSs) via its N-terminal membrane-binding domain, and undergoes oligomeric assembly at these sites through hydrophobic interactions among α-helix-1 and α-helix-2 of its C-terminal CHMP-like domain. CHMP7 is required for tethering ER to mitochondria and its depletion affects mitochondrial division independently of ESCRT complex activity. Live-cell imaging, super-resolution microscopy, domain deletion/mutation analysis, co-localization with ER and mitochondrial markers, CHMP7 depletion with mitochondrial division readout Cell death and differentiation Medium 35962186
2023 In C. elegans, the winged-helix domain of LEM-2 recruits CHMP-7 to the nuclear envelope, while a LEM-2-independent nucleoplasmic pool of CHMP-7 also contributes to NE stability. In the absence of BAF-LEM binding, LEM-2-CHMP-7 becomes essential for NE assembly and embryo survival, establishing that BAF-LEM and LEM-2-CHMP-7 represent distinct, redundant mechanisms for NE hole closure around spindle microtubules. C. elegans genetics (BAF-1, LEM-2, EMR-1 mutants), fluorescence imaging of NE permeability barrier, domain-specific rescue experiments Journal of cell science Medium 37795681
2024 SUN1 (LINC complex protein) physically interacts with CHMP7 and facilitates its nuclear localization in sporadic ALS iPSC-derived neurons; impaired NPC permeability barrier integrity and SUN1 interaction together drive CHMP7 nuclear translocation, initiating NPC injury cascades. iPSC-derived neuron model of sALS, co-immunoprecipitation, SUN1 knockdown with CHMP7 localization and NPC injury readouts Brain : a journal of neurology Medium 37639327
2024 CHMP2B promotes CHMP7-mediated nuclear pore complex injury in sALS neurons; CHMP2B-dependent 'activation' of the ESCRT-III nuclear surveillance pathway is sufficient to drive pathologic CHMP7 nuclear accumulation and POM121 nucleoporin reduction. Partial knockdown of CHMP2B alleviated NPC injury and TDP-43 dysfunction. iPSC-derived neuron model of sALS, CHMP2B knockdown with CHMP7 localization and NPC integrity readouts, TDP-43 functional assays Acta neuropathologica communications Medium 39709457
2024 IP-MS and CLIP analyses revealed that CHMP7 interacts with SmD1 (SMN complex component), small nuclear RNAs, and splicing factor mRNAs in motor neurons. Inhibition of the SmD1/SMN complex increases CHMP7 nuclear localization, while SmD1 overexpression restores CHMP7 cytoplasmic localization in ALS iPSC-MNs, establishing that RNA splicing integrity controls CHMP7 subcellular distribution. CRISPR-based microRaft screen (CRaft-ID), immunoprecipitation-mass spectrometry (IP-MS), enhanced CLIP (eCLIP), SmD1 overexpression rescue Neuron Medium 39486415
2026 Reduction of CHMP7 in mammalian cells causes DNA damage, heterochromatin disorganization, sister telomere associations, and telomere free ends. Genetic interaction analyses place CHMP7 in a common pathway with CHMP4B and AKTIP/Ft1 for telomere integrity, and in parallel routes to TNKS1; BAF1 and LEM2 also contribute to telomere safeguarding during NE reassembly. siRNA knockdown of CHMP7 and ESCRT components, fluorescence-based telomere integrity assays, genetic interaction analysis (double knockdowns) Cells Medium 41677621
2026 CHMP7 localizes to the nuclear envelope of cortical neurons in an activity-dependent manner, co-localizing with CHMP4B. shRNA-mediated Chmp7 knockdown reduces expression of activity-regulated genes and synaptic organization genes, and produces a transcriptome signature similar to Satb2 and Lemd2 loss-of-function, placing CHMP7 in a SATB2-LEMD2-CHMP7 tether linking chromatin architecture to activity-dependent gene regulation. shRNA knockdown in primary cortical neurons, RNA-seq transcriptome analysis, immunofluorescence localization during neuronal activity Biology Low 41744617

Source papers

Stage 0 corpus · 16 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 LEM2 recruits CHMP7 for ESCRT-mediated nuclear envelope closure in fission yeast and human cells. Proceedings of the National Academy of Sciences of the United States of America 157 28242692
2021 Nuclear accumulation of CHMP7 initiates nuclear pore complex injury and subsequent TDP-43 dysfunction in sporadic and familial ALS. Science translational medicine 109 34321318
2016 Membrane Binding by CHMP7 Coordinates ESCRT-III-Dependent Nuclear Envelope Reformation. Current biology : CB 106 27618263
2006 CHMP7, a novel ESCRT-III-related protein, associates with CHMP4b and functions in the endosomal sorting pathway. The Biochemical journal 59 16856878
2020 Regulated lipid synthesis and LEM2/CHMP7 jointly control nuclear envelope closure. The Journal of cell biology 55 32271860
2021 CDK1 controls CHMP7-dependent nuclear envelope reformation. eLife 36 34286694
2024 SUN1 facilitates CHMP7 nuclear influx and injury cascades in sporadic amyotrophic lateral sclerosis. Brain : a journal of neurology 27 37639327
2020 Functional validation of CHMP7 as an ADHD risk gene. Translational psychiatry 14 33159045
2016 Overexpression of CHMP7 from rapeseed and Arabidopsis causes dwarfism and premature senescence in Arabidopsis. Journal of plant physiology 10 27497741
2024 CHMP2B promotes CHMP7 mediated nuclear pore complex injury in sporadic ALS. Acta neuropathologica communications 8 39709457
2023 Nuclear envelope assembly relies on CHMP-7 in the absence of BAF-LEM-mediated hole closure. Journal of cell science 8 37795681
2022 Oligomeric CHMP7 mediates three-way ER junctions and ER-mitochondria interactions. Cell death and differentiation 8 35962186
2024 Inhibition of RNA splicing triggers CHMP7 nuclear entry, impacting TDP-43 function and leading to the onset of ALS cellular phenotypes. Neuron 7 39486415
2026 Reduced CHMP7 Expression Compromises Telomere Integrity in Mammalian Cells. Cells 0 41677621
2026 CHMP7/ESCRT-III Is Localized at the Nuclear Envelope of Cortical Neurons and Required for Expression of Activity-Regulated Genes. Biology 0 41744617
2023 Nuclear envelope assembly relies on CHMP-7 in the absence of BAF-LEM-mediated hole closure. bioRxiv : the preprint server for biology 0 37461528