Affinage

CHMP7

Charged multivesicular body protein 7 · UniProt Q8WUX9

Length
453 aa
Mass
50.9 kDa
Annotated
2026-06-09
16 papers in source corpus 13 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CHMP7 is an ESCRT-III-related protein that couples membrane binding to the assembly of downstream ESCRT-III machinery at the nuclear envelope and endoplasmic reticulum (PMID:16856878, PMID:27618263, PMID:28242692). It is built from N-terminal tandem Winged-Helix domains that constitute a membrane-binding module targeting the protein to the ER, and a C-terminal SNF7/CHMP-like domain that engages downstream ESCRT-III subunits including CHMP4b (PMID:16856878, PMID:27618263). The ER-resident pool provides the platform from which CHMP7 is enriched at the reforming nuclear envelope during mitotic exit, where the inner nuclear membrane protein LEM2 directly binds the CHMP7 C-terminus and acts as a site-specific adaptor recruiting CHMP7 and downstream factors (CHMP2A, IST1/CHMP8) to seal nuclear envelope holes (PMID:27618263, PMID:28242692). This recruitment is timed by CDK1 phosphorylation of CHMP7 at Ser3/Ser441 upon mitotic entry, which suppresses the LEM2 interaction and restrains assembly until telophase dephosphorylation licenses NE assembly while restricting inappropriate ER assembly (PMID:34286694). The LEM2–CHMP7 module is conserved and cooperates with BAF-LEM binding in redundant pathways for NE hole closure around spindle microtubules (PMID:32271860, PMID:37795681). Beyond mitotic NE reformation, CHMP7 acts at three-way ER junctions and ER-mitochondrial contact sites through its membrane-binding and C-terminal helices, influencing mitochondrial division independently of the canonical ESCRT complex (PMID:35962186), and contributes to telomere integrity and heterochromatin organization in a pathway shared with CHMP4B (PMID:41677621). Aberrant nuclear accumulation of CHMP7 — promoted by SUN1 interaction, impaired NPC permeability, and dysfunction of the SmD1/SMN splicing complex, and amplified by CHMP2B — overactivates ESCRT-III nuclear surveillance to reduce nucleoporins, disrupt Ran localization, and impair TDP-43 function, driving neurodegeneration in ALS iPSC-derived neurons (PMID:34321318, PMID:37639327, PMID:39709457, PMID:39486415).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2006 Medium

    Established CHMP7 as an ESCRT-III-related protein wired into the endosomal sorting pathway by showing its C-terminal half binds CHMP4b and that its disruption blocks cargo sorting and viral particle release.

    Evidence Pull-down from HEK-293T lysates, dominant-negative overexpression, and MLV Gag VLP release assay

    PMID:16856878

    Open questions at the time
    • No structural definition of the CHMP4b-binding interface
    • ER and nuclear envelope roles not yet identified
    • No in vitro reconstitution
  2. 2016 High

    Defined how CHMP7 reaches membranes by identifying its N-terminal tandem Winged-Helix domains as a membrane-binding module required for ER localization and subsequent NE recruitment of downstream ESCRT-III.

    Evidence Homology modeling, point mutagenesis, and live-cell imaging of localization and post-mitotic compartmentalization

    PMID:27618263

    Open questions at the time
    • Lipid specificity of the WH module not defined
    • Mechanism linking ER pool to NE enrichment incompletely resolved
  3. 2017 High

    Identified the molecular adaptor that targets CHMP7 to the nuclear envelope, showing LEM2 directly binds the CHMP7 C-terminus and places both factors upstream in a conserved ESCRT-III recruitment pathway.

    Evidence In vitro direct binding with recombinant proteins, S. pombe suppressor genetics in vps4Δ, and human cell siRNA/localization assays

    PMID:28242692

    Open questions at the time
    • Structure of the LEM2–CHMP7 complex not determined
    • How activation transitions from CHMP7 to CHMP2A/IST1 not detailed
  4. 2020 Medium

    Extended the LEM-2/CHMP-7 axis to meiotic NE closure and showed it restricts excess ER membrane during hole sealing, linking ESCRT-III to lipid synthesis control.

    Evidence C. elegans oocyte genetics, 3D electron microscopy, and nuclear permeability assays

    PMID:32271860

    Open questions at the time
    • Direct mechanism of ER membrane restriction unclear
    • Conservation of CNEP-1 parallel pathway in mammals untested
  5. 2021 High

    Resolved the cell-cycle timing of CHMP7 assembly by showing CDK1 phosphorylation at Ser3/Ser441 suppresses LEM2 binding during M-phase and that telophase dephosphorylation licenses NE assembly while restricting ER assembly.

    Evidence Phosphosite mapping, phosphomimetic/phospho-dead mutagenesis, co-IP, and live-cell imaging

    PMID:34286694

    Open questions at the time
    • Phosphatase responsible for telophase dephosphorylation not identified
    • Mechanism of LEM2 cluster dissolution by CHMP7 incompletely defined
  6. 2021 High

    Demonstrated that nuclear accumulation of CHMP7 is pathogenic, initiating NPC injury, Ran mislocalization, and TDP-43 dysfunction in ALS neurons, with knockdown reversing these defects.

    Evidence iPSC-derived spinal neuron models (C9orf72 and sporadic ALS), nuclear export inhibition, ASO knockdown, and viability assays

    PMID:34321318

    Open questions at the time
    • Which nucleoporins are direct targets of CHMP7-driven removal not fully defined
    • Trigger for nuclear mislocalization not yet identified in this study
  7. 2022 Medium

    Revealed an ESCRT-independent role for CHMP7 in shaping the ER and mitochondria, localizing it to three-way ER junctions and ER-mitochondrial contacts through its membrane-binding and C-terminal helices.

    Evidence Subcellular fractionation, super-resolution imaging, KO/knockdown, and domain/point mutagenesis with organelle morphology quantification

    PMID:35962186

    Open questions at the time
    • Not independently replicated
    • Relationship between this junction role and ESCRT-III assembly unclear
  8. 2023 Medium

    Dissected the recruitment logic at the NE, showing the LEM-2 winged-helix domain recruits CHMP-7 and that a LEM-2-independent nucleoplasmic CHMP-7 pool provides redundancy with BAF-LEM binding for NE assembly.

    Evidence C. elegans genetics with BAF-LEM and LEM-2/CHMP-7 mutants, fluorescence microscopy, permeability and embryo viability assays

    PMID:37795681

    Open questions at the time
    • Identity/regulation of the nucleoplasmic CHMP-7 pool unknown
    • Mammalian conservation of the redundancy not tested
  9. 2024 Medium

    Identified SUN1 as a driver of pathologic CHMP7 nuclear translocation, linking LINC complex interaction and NPC barrier loss to the ALS injury cascade.

    Evidence iPSC-derived sALS neuron model with SUN1 modulation, nuclear localization assays, and NPC integrity readouts

    PMID:37639327

    Open questions at the time
    • Direct SUN1–CHMP7 binding not biochemically validated
    • Single lab, single model system
  10. 2024 Medium

    Showed that CHMP2B promotes and is required for the overactivated nuclear ESCRT-III surveillance underlying ALS NPC injury, identifying a tractable upstream node.

    Evidence iPSC-derived sALS neurons with CHMP2B knockdown, immunofluorescence for CHMP7/POM121, and TDP-43 assays

    PMID:39709457

    Open questions at the time
    • Mechanism by which CHMP2B sustains CHMP7 activation unresolved
    • Not independently replicated
  11. 2024 High

    Placed RNA splicing regulation upstream of CHMP7 localization by showing CHMP7 associates with SmD1, snRNAs, and splicing factor mRNAs, and that SmD1 restores cytoplasmic CHMP7 and corrects STMN2 splicing.

    Evidence CRaft-ID RNA-binding protein screen, IP-MS, eCLIP, and SmD1 knockdown/overexpression rescue in ALS iPSC motor neurons

    PMID:39486415

    Open questions at the time
    • Whether CHMP7 RNA binding is direct or complex-mediated unresolved
    • How splicing dysfunction mechanistically forces nuclear retention unclear
  12. 2026 Medium

    Extended CHMP7's NE reassembly function to genome integrity, linking its loss to DNA damage, heterochromatin disorganization, and telomere defects in a pathway shared with CHMP4B.

    Evidence CHMP7 knockdown in mammalian cells, γH2AX and telomere FISH, and genetic epistasis with CHMP4B/AKTIP/TNKS1/BAF1/LEM2

    PMID:41677621

    Open questions at the time
    • Direct vs indirect role at telomeres unresolved
    • Not independently replicated
  13. 2026 Medium

    Connected NE-localized CHMP7 to activity-dependent transcription, placing it in a SATB2-LEMD2-CHMP7 chromatin tether that regulates synaptic and activity-regulated genes in cortical neurons.

    Evidence shRNA Chmp7 knockdown in primary cortical neurons, RNA-seq, NE localization imaging, and comparison with Satb2/Lemd2 loss models

    PMID:41744617

    Open questions at the time
    • Direct involvement of CHMP7 in chromatin tethering not biochemically shown
    • Not independently replicated

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown how the same CHMP7 membrane-sealing activity is partitioned between physiological NE/ER functions and pathological nuclear surveillance, and what governs the decision to retain CHMP7 in the nucleus.
  • No structural model of nuclear CHMP7 oligomers driving NPC injury
  • Switch between cytoplasmic and nuclear pools incompletely defined
  • Direct nucleoporin substrates of CHMP7-driven removal not enumerated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 2 GO:0060090 molecular adaptor activity 2 GO:0003723 RNA binding 1
Localization
GO:0005635 nuclear envelope 4 GO:0005634 nucleus 3 GO:0005783 endoplasmic reticulum 2 GO:0005739 mitochondrion 1 GO:0005768 endosome 1
Pathway
R-HSA-1643685 Disease 3 R-HSA-1852241 Organelle biogenesis and maintenance 3 R-HSA-1640170 Cell Cycle 2 R-HSA-5653656 Vesicle-mediated transport 1
Partners
CHMP2ACHMP2BCHMP4BIST1LEM2SMD1SUN1
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 containing an SNF7 domain and a distantly SNF7-related domain; its C-terminal half directly interacts with CHMP4b (but not EAP20) as shown by pull-down assay from HEK-293T cell lysates. Overexpressed GFP-CHMP7 caused accumulation of ubiquitinated proteins and endocytosed EGF, and exerted a dominant-negative effect on MLV Gag virus-like particle release, indicating a functional role in the endosomal sorting pathway. Pull-down assay (Strep-tag/GFP co-precipitation from HEK-293T lysates), confocal fluorescence microscopy, dominant-negative overexpression, 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 enables CHMP7 to associate with the ER. This ER localization provides the platform for CHMP7 enrichment at the reforming nuclear envelope during mitotic exit. Point mutations in the N-terminus that disrupt membrane binding prevent ER localization, NE recruitment of downstream ESCRT-III components, and proper post-mitotic nucleo-cytoplasmic compartmentalization. Homology modeling, structure-function analysis with point mutagenesis, live-cell imaging, fluorescence microscopy 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. In fission yeast, genetic epistasis (suppressor screens in vps4Δ background) placed Lem2p and Cmp7p upstream in the same pathway; loss-of-function mutations in lem2 or cmp7 suppress nuclear morphology/integrity defects caused by vps4 deletion. In vitro direct binding assay (recombinant C-terminal LEM2 domain + CHMP7), genetic epistasis (spontaneous suppressor analysis in S. pombe), live-cell imaging during NE reformation in human cells, siRNA knockdown of LEM2 with ESCRT factor localization readout Proceedings of the National Academy of Sciences of the United States of America High 28242692
2020 In C. elegans oocytes, LEM-2 and CHMP-7 (orthologs of LEM2 and CHMP7) work together to close NE holes surrounding meiotic spindle microtubules; loss of NE adaptors for ESCRT-III (including LEM-2) exacerbates ER invasion and nuclear permeability defects caused by loss of glycerolipid synthesis regulator CNEP-1, placing ESCRT-III (via CHMP-7) in a parallel mechanism that restricts excess ER membrane during NE closure. C. elegans genetics (loss-of-function mutants, epistasis analysis), 3D electron microscopy, nuclear permeability assays The Journal of cell biology Medium 32271860
2021 Nuclear accumulation of CHMP7 initiates nuclear pore complex (NPC) injury by reducing specific nucleoporins, disrupting Ran GTPase localization, and impairing TDP-43-associated mRNA expression in human ALS iPSC-derived spinal neurons. Inhibiting nuclear export of CHMP7 was sufficient to trigger these events, and CHMP7 knockdown alleviated all downstream pathological changes including glutamate-induced neuronal death. iPSC-derived neuron model (C9orf72 ALS and sporadic ALS), CHMP7 nuclear export inhibition, antisense oligonucleotide knockdown, immunofluorescence for Nups and Ran, RNA expression analysis, cell viability assay Science translational medicine High 34321318
2021 CDK1 phosphorylates CHMP7 at Ser3 and Ser441 upon mitotic entry, reducing CHMP7's interaction with LEM2 and limiting CHMP7 assembly during M-phase. Spatiotemporal dephosphorylation of CHMP7 at telophase licenses its assembly at the reforming NE but restricts its assembly on the peripheral ER. Without CDK1 phosphorylation, CHMP7 undergoes inappropriate ER assembly during M-exit, capturing LEM2 and downstream ESCRT-III components. CHMP7 also plays a role in dissolution of LEM2 clusters that form at the NE during M-exit. Live-cell imaging, protein biochemistry (phosphorylation site mapping, in vitro CDK1 kinase assay implied), phosphomimetic/phospho-dead mutagenesis, co-immunoprecipitation eLife High 34286694
2022 CHMP7 localizes to ER three-way junctions, mitochondria-associated membranes (MAMs), and the outer mitochondrial membrane via its N-terminal membrane-binding domain. CHMP7 undergoes dynamic oligomeric assembly at three-way ER junctions and ER-mitochondrial membrane contact sites through hydrophobic interactions among α-helix-1 and α-helix-2 of its C-terminal CHMP-like domain. CHMP7 mediates formation of three-way ER junctions in parallel with Atlastins and regulates ER-mitochondrial interactions; its depletion affects mitochondrial division independently of the ESCRT complex. Subcellular fractionation, super-resolution and confocal fluorescence microscopy, CHMP7 knockdown/knockout, domain deletion and point mutagenesis, organelle morphology quantification Cell death and differentiation Medium 35962186
2023 In C. elegans, the winged-helix (WH) domain of LEM-2 recruits CHMP-7 to the nuclear envelope; a LEM-2-independent nucleoplasmic pool of CHMP-7 also contributes to NE stability. BAF-LEM binding and LEM-2-CHMP-7 have distinct, redundant roles in NE hole closure around spindle microtubules, and in the absence of BAF-LEM binding, LEM-2-CHMP-7 becomes essential for NE assembly and embryo survival. C. elegans genetics (BAF-LEM binding mutants, LEM-2/CHMP-7 double mutants, epistasis), fluorescence microscopy, nuclear permeability assays, embryo viability assays Journal of cell science Medium 37795681
2024 SUN1 (a LINC complex protein) facilitates CHMP7 nuclear localization in sporadic ALS iPSC-derived neurons; impaired NPC permeability barrier integrity and interaction with SUN1 together drive aberrant nuclear translocation/retention of CHMP7, which then initiates NPC injury cascades. iPSC-derived neuron model of sALS, SUN1 knockdown/modulation, nuclear localization assays, NPC integrity readouts (nucleoporin levels, TDP-43 localization) Brain : a journal of neurology Medium 37639327
2024 CHMP2B promotes CHMP7-mediated NPC injury in sporadic ALS neurons; CHMP7/ESCRT-III nuclear surveillance is overactivated in sALS and this overactivation depends on CHMP2B. Sustained CHMP2B-dependent activation is sufficient to drive pathologic CHMP7 nuclear accumulation and POM121 nucleoporin reduction; partial CHMP2B knockdown alleviates NPC injury and downstream TDP-43 dysfunction. iPSC-derived neuron model of sALS, CHMP2B knockdown, immunofluorescence for CHMP7 localization and POM121, TDP-43 localization/function assays Acta neuropathologica communications Medium 39709457
2024 CHMP7 physically interacts with SmD1 (a survival of motor neuron complex component), small nuclear RNAs, and splicing factor mRNAs in motor neurons, as revealed by IP-MS and eCLIP. Inhibiting the SmD1/SMN complex increases CHMP7 nuclear localization, and overexpression of SmD1 in ALS iPSC motor neurons restores CHMP7 cytoplasmic localization and corrects STMN2 splicing, placing RNA splicing regulation upstream of CHMP7 nuclear localization. CRISPR-based microRaft screen (CRaft-ID) of 55 RNA-binding proteins, immunoprecipitation-mass spectrometry (IP-MS), enhanced crosslinking and immunoprecipitation (eCLIP), SmD1 knockdown/overexpression in ALS iPSC motor neurons Neuron High 39486415
2026 Reduction of CHMP7 in mammalian cells causes DNA damage, heterochromatin disorganization, and telomere defects including sister telomere associations and telomere-free ends. Genetic interaction analyses place CHMP7 in a common pathway with CHMP4B and AKTIP/Ft1, and in a parallel pathway to TNKS1 (a TRF1 regulator), suggesting CHMP7's role in NE reassembly extends to telomere integrity maintenance. CHMP7 knockdown in mammalian cells, DNA damage assays (γH2AX), telomere FISH, genetic epistasis with CHMP4B/AKTIP/TNKS1/BAF1/LEM2 Cells Medium 41677621
2026 In cortical neurons, CHMP7 localizes to the nuclear envelope and its knockdown reduces expression of activity-regulated genes and genes involved in synaptic organization/trans-synaptic signaling, placing CHMP7 within a SATB2-LEMD2-CHMP7 chromatin tether that links nuclear envelope plasticity to activity-dependent transcription. shRNA-mediated Chmp7 knockdown in primary cortical neurons, immunofluorescence/confocal microscopy for NE localization of CHMP7 and CHMP4B, transcriptome analysis (RNA-seq), comparison with Satb2 and Lemd2 loss-of-function models Biology Medium 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 160 28242692
2021 Nuclear accumulation of CHMP7 initiates nuclear pore complex injury and subsequent TDP-43 dysfunction in sporadic and familial ALS. Science translational medicine 117 34321318
2016 Membrane Binding by CHMP7 Coordinates ESCRT-III-Dependent Nuclear Envelope Reformation. Current biology : CB 109 27618263
2006 CHMP7, a novel ESCRT-III-related protein, associates with CHMP4b and functions in the endosomal sorting pathway. The Biochemical journal 61 16856878
2020 Regulated lipid synthesis and LEM2/CHMP7 jointly control nuclear envelope closure. The Journal of cell biology 57 32271860
2021 CDK1 controls CHMP7-dependent nuclear envelope reformation. eLife 37 34286694
2024 SUN1 facilitates CHMP7 nuclear influx and injury cascades in sporadic amyotrophic lateral sclerosis. Brain : a journal of neurology 28 37639327
2020 Functional validation of CHMP7 as an ADHD risk gene. Translational psychiatry 14 33159045
2022 Oligomeric CHMP7 mediates three-way ER junctions and ER-mitochondria interactions. Cell death and differentiation 9 35962186
2024 Inhibition of RNA splicing triggers CHMP7 nuclear entry, impacting TDP-43 function and leading to the onset of ALS cellular phenotypes. Neuron 8 39486415
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
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
2026 Correction: Burla et al. Reduced CHMP7 Expression Compromises Telomere Integrity in Mammalian Cells. Cells 2026, 15, 256. Cells 0 42193965
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

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