{"gene":"CHMP7","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2006,"finding":"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.","method":"Pull-down assay (Strep-tag/GFP co-precipitation from HEK-293T lysates), confocal fluorescence microscopy, dominant-negative overexpression, virus-like particle release assay","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, multiple orthogonal methods (pull-down, dominant-negative phenotype, VLP assay), but no in vitro reconstitution or structural validation","pmids":["16856878"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Homology modeling, structure-function analysis with point mutagenesis, live-cell imaging, fluorescence microscopy","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — mutagenesis plus multiple functional readouts (ER localization, NE recruitment, compartmentalization) in a single focused study","pmids":["27618263"],"is_preprint":false},{"year":2017,"finding":"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.","method":"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","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro direct binding, genetic epistasis in yeast, and human cell functional assays across two independent experimental systems and two labs","pmids":["28242692"],"is_preprint":false},{"year":2020,"finding":"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.","method":"C. elegans genetics (loss-of-function mutants, epistasis analysis), 3D electron microscopy, nuclear permeability assays","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with morphological and permeability readouts in a model organism, single lab","pmids":["32271860"],"is_preprint":false},{"year":2021,"finding":"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.","method":"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","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain- and loss-of-function in human neurons with multiple orthogonal mechanistic readouts (Nup levels, Ran localization, mRNA expression, cell survival), replicated across familial and sporadic ALS models","pmids":["34321318"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Live-cell imaging, protein biochemistry (phosphorylation site mapping, in vitro CDK1 kinase assay implied), phosphomimetic/phospho-dead mutagenesis, co-immunoprecipitation","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — phosphorylation sites identified with mutagenesis, interaction assays, and live imaging, multiple orthogonal methods in a single focused study","pmids":["34286694"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Subcellular fractionation, super-resolution and confocal fluorescence microscopy, CHMP7 knockdown/knockout, domain deletion and point mutagenesis, organelle morphology quantification","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — multiple orthogonal methods (localization, mutagenesis, KO phenotype) in a single lab, novel function not yet independently replicated","pmids":["35962186"],"is_preprint":false},{"year":2023,"finding":"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.","method":"C. elegans genetics (BAF-LEM binding mutants, LEM-2/CHMP-7 double mutants, epistasis), fluorescence microscopy, nuclear permeability assays, embryo viability assays","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with multiple alleles and fluorescence-based localization readouts, single lab","pmids":["37795681"],"is_preprint":false},{"year":2024,"finding":"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.","method":"iPSC-derived neuron model of sALS, SUN1 knockdown/modulation, nuclear localization assays, NPC integrity readouts (nucleoporin levels, TDP-43 localization)","journal":"Brain : a journal of neurology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — functional genetic perturbation with mechanistic pathway readouts in a human neuron model, single lab","pmids":["37639327"],"is_preprint":false},{"year":2024,"finding":"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.","method":"iPSC-derived neuron model of sALS, CHMP2B knockdown, immunofluorescence for CHMP7 localization and POM121, TDP-43 localization/function assays","journal":"Acta neuropathologica communications","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — loss-of-function with multiple mechanistic readouts in human neurons, single lab","pmids":["39709457"],"is_preprint":false},{"year":2024,"finding":"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.","method":"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","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — IP-MS and eCLIP together with functional rescue experiment, multiple orthogonal methods in a single focused study","pmids":["39486415"],"is_preprint":false},{"year":2026,"finding":"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.","method":"CHMP7 knockdown in mammalian cells, DNA damage assays (γH2AX), telomere FISH, genetic epistasis with CHMP4B/AKTIP/TNKS1/BAF1/LEM2","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — multiple readouts (DNA damage, telomere FISH, epistasis) from a single lab with no independent replication yet","pmids":["41677621"],"is_preprint":false},{"year":2026,"finding":"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.","method":"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","journal":"Biology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — loss-of-function with transcriptomic readout and localization data, single lab, novel function not yet independently replicated","pmids":["41744617"],"is_preprint":false}],"current_model":"CHMP7 is an ESCRT-II/ESCRT-III hybrid protein whose N-terminal tandem Winged-Helix domains mediate membrane binding at the ER; during mitotic exit, LEM2 (inner nuclear membrane) directly recruits CHMP7 to nuclear envelope holes to initiate ESCRT-III assembly (via CHMP4b, CHMP2A, IST1/CHMP8) and seal the reforming NE, a process timed by CDK1 phosphorylation of CHMP7 at Ser3/Ser441 that suppresses its LEM2 interaction during M-phase; in interphase CHMP7 additionally mediates three-way ER junctions and ER-mitochondrial contacts, participates in NPC quality control surveillance (promoted by CHMP2B), and when aberrantly nuclear (driven by SUN1 interaction and SMN complex dysfunction) initiates nucleoporin loss, TDP-43 dysfunction, and neurodegeneration as seen in ALS."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2006,"claim":"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","pmids":["16856878"],"confidence":"Medium","gaps":["No structural definition of the CHMP4b-binding interface","ER and nuclear envelope roles not yet identified","No in vitro reconstitution"]},{"year":2016,"claim":"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","pmids":["27618263"],"confidence":"High","gaps":["Lipid specificity of the WH module not defined","Mechanism linking ER pool to NE enrichment incompletely resolved"]},{"year":2017,"claim":"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","pmids":["28242692"],"confidence":"High","gaps":["Structure of the LEM2–CHMP7 complex not determined","How activation transitions from CHMP7 to CHMP2A/IST1 not detailed"]},{"year":2020,"claim":"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","pmids":["32271860"],"confidence":"Medium","gaps":["Direct mechanism of ER membrane restriction unclear","Conservation of CNEP-1 parallel pathway in mammals untested"]},{"year":2021,"claim":"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","pmids":["34286694"],"confidence":"High","gaps":["Phosphatase responsible for telophase dephosphorylation not identified","Mechanism of LEM2 cluster dissolution by CHMP7 incompletely defined"]},{"year":2021,"claim":"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","pmids":["34321318"],"confidence":"High","gaps":["Which nucleoporins are direct targets of CHMP7-driven removal not fully defined","Trigger for nuclear mislocalization not yet identified in this study"]},{"year":2022,"claim":"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","pmids":["35962186"],"confidence":"Medium","gaps":["Not independently replicated","Relationship between this junction role and ESCRT-III assembly unclear"]},{"year":2023,"claim":"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","pmids":["37795681"],"confidence":"Medium","gaps":["Identity/regulation of the nucleoplasmic CHMP-7 pool unknown","Mammalian conservation of the redundancy not tested"]},{"year":2024,"claim":"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","pmids":["37639327"],"confidence":"Medium","gaps":["Direct SUN1–CHMP7 binding not biochemically validated","Single lab, single model system"]},{"year":2024,"claim":"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","pmids":["39709457"],"confidence":"Medium","gaps":["Mechanism by which CHMP2B sustains CHMP7 activation unresolved","Not independently replicated"]},{"year":2024,"claim":"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","pmids":["39486415"],"confidence":"High","gaps":["Whether CHMP7 RNA binding is direct or complex-mediated unresolved","How splicing dysfunction mechanistically forces nuclear retention unclear"]},{"year":2026,"claim":"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","pmids":["41677621"],"confidence":"Medium","gaps":["Direct vs indirect role at telomeres unresolved","Not independently replicated"]},{"year":2026,"claim":"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","pmids":["41744617"],"confidence":"Medium","gaps":["Direct involvement of CHMP7 in chromatin tethering not biochemically shown","Not independently replicated"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[1,6]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[10]}],"localization":[{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[1,2,5,12]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1,6]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[6]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,8,10]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[2,5]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[1,2,6]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,8,9]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0]}],"complexes":["ESCRT-III"],"partners":["CHMP4B","LEM2","CHMP2A","IST1","SUN1","CHMP2B","SMD1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8WUX9","full_name":"Charged multivesicular body protein 7","aliases":["Chromatin-modifying protein 7"],"length_aa":453,"mass_kda":50.9,"function":"ESCRT-III-like protein required to recruit the ESCRT-III complex to the nuclear envelope (NE) during late anaphase (PubMed:26040712). Together with SPAST, the ESCRT-III complex promotes NE sealing and mitotic spindle disassembly during late anaphase (PubMed:26040712, PubMed:28242692). Recruited to the reforming NE during anaphase by LEMD2 (PubMed:28242692). Plays a role in the endosomal sorting pathway (PubMed:16856878)","subcellular_location":"Cytoplasm; Nucleus envelope; Nucleus envelope","url":"https://www.uniprot.org/uniprotkb/Q8WUX9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/CHMP7","classification":"Common Essential","n_dependent_lines":830,"n_total_lines":1208,"dependency_fraction":0.6870860927152318},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000147457","cell_line_id":"CID000779","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"vesicles","grade":2},{"compartment":"er","grade":1}],"interactors":[{"gene":"C8ORF33","stoichiometry":0.2},{"gene":"NUP54","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000779","total_profiled":1310},"omim":[{"mim_id":"616312","title":"LEM DOMAIN-CONTAINING PROTEIN 2; LEMD2","url":"https://www.omim.org/entry/616312"},{"mim_id":"611130","title":"CHARGED MULTIVESICULAR BODY PROTEIN 7; CHMP7","url":"https://www.omim.org/entry/611130"},{"mim_id":"609982","title":"VACUOLAR PROTEIN SORTING 4 HOMOLOG A; VPS4A","url":"https://www.omim.org/entry/609982"},{"mim_id":"604277","title":"SPASTIN; SPAST","url":"https://www.omim.org/entry/604277"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":30.5}],"url":"https://www.proteinatlas.org/search/CHMP7"},"hgnc":{"alias_symbol":["MGC29816"],"prev_symbol":[]},"alphafold":{"accession":"Q8WUX9","domains":[{"cath_id":"-","chopping":"237-367_379-391","consensus_level":"high","plddt":85.7409,"start":237,"end":391}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WUX9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WUX9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WUX9-F1-predicted_aligned_error_v6.png","plddt_mean":76.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CHMP7","jax_strain_url":"https://www.jax.org/strain/search?query=CHMP7"},"sequence":{"accession":"Q8WUX9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8WUX9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8WUX9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WUX9"}},"corpus_meta":[{"pmid":"28242692","id":"PMC_28242692","title":"LEM2 recruits CHMP7 for ESCRT-mediated nuclear envelope closure in fission yeast and human cells.","date":"2017","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/28242692","citation_count":160,"is_preprint":false},{"pmid":"34321318","id":"PMC_34321318","title":"Nuclear accumulation of CHMP7 initiates nuclear pore complex injury and subsequent TDP-43 dysfunction in sporadic and familial ALS.","date":"2021","source":"Science translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34321318","citation_count":117,"is_preprint":false},{"pmid":"27618263","id":"PMC_27618263","title":"Membrane Binding by CHMP7 Coordinates ESCRT-III-Dependent Nuclear Envelope Reformation.","date":"2016","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/27618263","citation_count":109,"is_preprint":false},{"pmid":"16856878","id":"PMC_16856878","title":"CHMP7, a novel ESCRT-III-related protein, associates with CHMP4b and functions in the endosomal sorting pathway.","date":"2006","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/16856878","citation_count":61,"is_preprint":false},{"pmid":"32271860","id":"PMC_32271860","title":"Regulated lipid synthesis and LEM2/CHMP7 jointly control nuclear envelope closure.","date":"2020","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/32271860","citation_count":57,"is_preprint":false},{"pmid":"34286694","id":"PMC_34286694","title":"CDK1 controls CHMP7-dependent nuclear envelope reformation.","date":"2021","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/34286694","citation_count":37,"is_preprint":false},{"pmid":"37639327","id":"PMC_37639327","title":"SUN1 facilitates CHMP7 nuclear influx and injury cascades in sporadic amyotrophic lateral sclerosis.","date":"2024","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/37639327","citation_count":28,"is_preprint":false},{"pmid":"33159045","id":"PMC_33159045","title":"Functional validation of CHMP7 as an ADHD risk gene.","date":"2020","source":"Translational psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/33159045","citation_count":14,"is_preprint":false},{"pmid":"35962186","id":"PMC_35962186","title":"Oligomeric CHMP7 mediates three-way ER junctions and ER-mitochondria interactions.","date":"2022","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/35962186","citation_count":9,"is_preprint":false},{"pmid":"39486415","id":"PMC_39486415","title":"Inhibition of RNA splicing triggers CHMP7 nuclear entry, impacting TDP-43 function and leading to the onset of ALS cellular phenotypes.","date":"2024","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/39486415","citation_count":8,"is_preprint":false},{"pmid":"39709457","id":"PMC_39709457","title":"CHMP2B promotes CHMP7 mediated nuclear pore complex injury in sporadic ALS.","date":"2024","source":"Acta neuropathologica communications","url":"https://pubmed.ncbi.nlm.nih.gov/39709457","citation_count":8,"is_preprint":false},{"pmid":"37795681","id":"PMC_37795681","title":"Nuclear envelope assembly relies on CHMP-7 in the absence of BAF-LEM-mediated hole closure.","date":"2023","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/37795681","citation_count":8,"is_preprint":false},{"pmid":"41744617","id":"PMC_41744617","title":"CHMP7/ESCRT-III Is Localized at the Nuclear Envelope of Cortical Neurons and Required for Expression of Activity-Regulated Genes.","date":"2026","source":"Biology","url":"https://pubmed.ncbi.nlm.nih.gov/41744617","citation_count":0,"is_preprint":false},{"pmid":"41677621","id":"PMC_41677621","title":"Reduced CHMP7 Expression Compromises Telomere Integrity in Mammalian Cells.","date":"2026","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/41677621","citation_count":0,"is_preprint":false},{"pmid":"37461528","id":"PMC_37461528","title":"Nuclear envelope assembly relies on CHMP-7 in the absence of BAF-LEM-mediated hole closure.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/37461528","citation_count":0,"is_preprint":false},{"pmid":"42193965","id":"PMC_42193965","title":"Correction: Burla et al. Reduced CHMP7 Expression Compromises Telomere Integrity in Mammalian Cells. Cells 2026, 15, 256.","date":"2026","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/42193965","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9493,"output_tokens":4096,"usd":0.044959,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11979,"output_tokens":4705,"usd":0.08876,"stage2_stop_reason":"end_turn"},"total_usd":0.133719,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Pull-down assay (Strep-tag/GFP co-precipitation from HEK-293T lysates), confocal fluorescence microscopy, dominant-negative overexpression, virus-like particle release assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, multiple orthogonal methods (pull-down, dominant-negative phenotype, VLP assay), but no in vitro reconstitution or structural validation\",\n      \"pmids\": [\"16856878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Homology modeling, structure-function analysis with point mutagenesis, live-cell imaging, fluorescence microscopy\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mutagenesis plus multiple functional readouts (ER localization, NE recruitment, compartmentalization) in a single focused study\",\n      \"pmids\": [\"27618263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro direct binding, genetic epistasis in yeast, and human cell functional assays across two independent experimental systems and two labs\",\n      \"pmids\": [\"28242692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"C. elegans genetics (loss-of-function mutants, epistasis analysis), 3D electron microscopy, nuclear permeability assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with morphological and permeability readouts in a model organism, single lab\",\n      \"pmids\": [\"32271860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain- and loss-of-function in human neurons with multiple orthogonal mechanistic readouts (Nup levels, Ran localization, mRNA expression, cell survival), replicated across familial and sporadic ALS models\",\n      \"pmids\": [\"34321318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Live-cell imaging, protein biochemistry (phosphorylation site mapping, in vitro CDK1 kinase assay implied), phosphomimetic/phospho-dead mutagenesis, co-immunoprecipitation\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — phosphorylation sites identified with mutagenesis, interaction assays, and live imaging, multiple orthogonal methods in a single focused study\",\n      \"pmids\": [\"34286694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Subcellular fractionation, super-resolution and confocal fluorescence microscopy, CHMP7 knockdown/knockout, domain deletion and point mutagenesis, organelle morphology quantification\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — multiple orthogonal methods (localization, mutagenesis, KO phenotype) in a single lab, novel function not yet independently replicated\",\n      \"pmids\": [\"35962186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"C. elegans genetics (BAF-LEM binding mutants, LEM-2/CHMP-7 double mutants, epistasis), fluorescence microscopy, nuclear permeability assays, embryo viability assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with multiple alleles and fluorescence-based localization readouts, single lab\",\n      \"pmids\": [\"37795681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"iPSC-derived neuron model of sALS, SUN1 knockdown/modulation, nuclear localization assays, NPC integrity readouts (nucleoporin levels, TDP-43 localization)\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — functional genetic perturbation with mechanistic pathway readouts in a human neuron model, single lab\",\n      \"pmids\": [\"37639327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"iPSC-derived neuron model of sALS, CHMP2B knockdown, immunofluorescence for CHMP7 localization and POM121, TDP-43 localization/function assays\",\n      \"journal\": \"Acta neuropathologica communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — loss-of-function with multiple mechanistic readouts in human neurons, single lab\",\n      \"pmids\": [\"39709457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — IP-MS and eCLIP together with functional rescue experiment, multiple orthogonal methods in a single focused study\",\n      \"pmids\": [\"39486415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"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.\",\n      \"method\": \"CHMP7 knockdown in mammalian cells, DNA damage assays (γH2AX), telomere FISH, genetic epistasis with CHMP4B/AKTIP/TNKS1/BAF1/LEM2\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — multiple readouts (DNA damage, telomere FISH, epistasis) from a single lab with no independent replication yet\",\n      \"pmids\": [\"41677621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — loss-of-function with transcriptomic readout and localization data, single lab, novel function not yet independently replicated\",\n      \"pmids\": [\"41744617\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CHMP7 is an ESCRT-II/ESCRT-III hybrid protein whose N-terminal tandem Winged-Helix domains mediate membrane binding at the ER; during mitotic exit, LEM2 (inner nuclear membrane) directly recruits CHMP7 to nuclear envelope holes to initiate ESCRT-III assembly (via CHMP4b, CHMP2A, IST1/CHMP8) and seal the reforming NE, a process timed by CDK1 phosphorylation of CHMP7 at Ser3/Ser441 that suppresses its LEM2 interaction during M-phase; in interphase CHMP7 additionally mediates three-way ER junctions and ER-mitochondrial contacts, participates in NPC quality control surveillance (promoted by CHMP2B), and when aberrantly nuclear (driven by SUN1 interaction and SMN complex dysfunction) initiates nucleoporin loss, TDP-43 dysfunction, and neurodegeneration as seen in ALS.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #1, #2]. 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 [#0, #1]. 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 [#1, #2]. 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 [#5]. The LEM2–CHMP7 module is conserved and cooperates with BAF-LEM binding in redundant pathways for NE hole closure around spindle microtubules [#3, #7]. 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 [#6], and contributes to telomere integrity and heterochromatin organization in a pathway shared with CHMP4B [#11]. 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 [#4, #8, #9, #10].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"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.\",\n      \"evidence\": \"Pull-down from HEK-293T lysates, dominant-negative overexpression, and MLV Gag VLP release assay\",\n      \"pmids\": [\"16856878\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural definition of the CHMP4b-binding interface\", \"ER and nuclear envelope roles not yet identified\", \"No in vitro reconstitution\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"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.\",\n      \"evidence\": \"Homology modeling, point mutagenesis, and live-cell imaging of localization and post-mitotic compartmentalization\",\n      \"pmids\": [\"27618263\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Lipid specificity of the WH module not defined\", \"Mechanism linking ER pool to NE enrichment incompletely resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro direct binding with recombinant proteins, S. pombe suppressor genetics in vps4Δ, and human cell siRNA/localization assays\",\n      \"pmids\": [\"28242692\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the LEM2–CHMP7 complex not determined\", \"How activation transitions from CHMP7 to CHMP2A/IST1 not detailed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"C. elegans oocyte genetics, 3D electron microscopy, and nuclear permeability assays\",\n      \"pmids\": [\"32271860\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mechanism of ER membrane restriction unclear\", \"Conservation of CNEP-1 parallel pathway in mammals untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"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.\",\n      \"evidence\": \"Phosphosite mapping, phosphomimetic/phospho-dead mutagenesis, co-IP, and live-cell imaging\",\n      \"pmids\": [\"34286694\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphatase responsible for telophase dephosphorylation not identified\", \"Mechanism of LEM2 cluster dissolution by CHMP7 incompletely defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"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.\",\n      \"evidence\": \"iPSC-derived spinal neuron models (C9orf72 and sporadic ALS), nuclear export inhibition, ASO knockdown, and viability assays\",\n      \"pmids\": [\"34321318\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which nucleoporins are direct targets of CHMP7-driven removal not fully defined\", \"Trigger for nuclear mislocalization not yet identified in this study\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"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.\",\n      \"evidence\": \"Subcellular fractionation, super-resolution imaging, KO/knockdown, and domain/point mutagenesis with organelle morphology quantification\",\n      \"pmids\": [\"35962186\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Not independently replicated\", \"Relationship between this junction role and ESCRT-III assembly unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"C. elegans genetics with BAF-LEM and LEM-2/CHMP-7 mutants, fluorescence microscopy, permeability and embryo viability assays\",\n      \"pmids\": [\"37795681\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity/regulation of the nucleoplasmic CHMP-7 pool unknown\", \"Mammalian conservation of the redundancy not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified SUN1 as a driver of pathologic CHMP7 nuclear translocation, linking LINC complex interaction and NPC barrier loss to the ALS injury cascade.\",\n      \"evidence\": \"iPSC-derived sALS neuron model with SUN1 modulation, nuclear localization assays, and NPC integrity readouts\",\n      \"pmids\": [\"37639327\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct SUN1–CHMP7 binding not biochemically validated\", \"Single lab, single model system\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed that CHMP2B promotes and is required for the overactivated nuclear ESCRT-III surveillance underlying ALS NPC injury, identifying a tractable upstream node.\",\n      \"evidence\": \"iPSC-derived sALS neurons with CHMP2B knockdown, immunofluorescence for CHMP7/POM121, and TDP-43 assays\",\n      \"pmids\": [\"39709457\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which CHMP2B sustains CHMP7 activation unresolved\", \"Not independently replicated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"evidence\": \"CRaft-ID RNA-binding protein screen, IP-MS, eCLIP, and SmD1 knockdown/overexpression rescue in ALS iPSC motor neurons\",\n      \"pmids\": [\"39486415\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CHMP7 RNA binding is direct or complex-mediated unresolved\", \"How splicing dysfunction mechanistically forces nuclear retention unclear\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"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.\",\n      \"evidence\": \"CHMP7 knockdown in mammalian cells, γH2AX and telomere FISH, and genetic epistasis with CHMP4B/AKTIP/TNKS1/BAF1/LEM2\",\n      \"pmids\": [\"41677621\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect role at telomeres unresolved\", \"Not independently replicated\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"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.\",\n      \"evidence\": \"shRNA Chmp7 knockdown in primary cortical neurons, RNA-seq, NE localization imaging, and comparison with Satb2/Lemd2 loss models\",\n      \"pmids\": [\"41744617\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct involvement of CHMP7 in chromatin tethering not biochemically shown\", \"Not independently replicated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [1, 6]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [1, 2, 5, 12]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1, 6]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 8, 10]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [2, 5]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [1, 2, 6]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 8, 9]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\"ESCRT-III\"],\n    \"partners\": [\"CHMP4B\", \"LEM2\", \"CHMP2A\", \"IST1\", \"SUN1\", \"CHMP2B\", \"SmD1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}