{"gene":"CHMP7","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2006,"finding":"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.","method":"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","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal pulldown with domain mapping, functional VLP assay; single lab","pmids":["16856878"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Homology modeling, structure-function analysis with point mutations, live-cell imaging, membrane-binding assays, nuclear envelope reformation assay","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 1-2 — mutagenesis of defined domain combined with functional rescue and imaging; moderate evidence from single lab with multiple orthogonal methods","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. 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.","method":"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)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — direct in vitro binding, genetic epistasis in yeast, and functional knockdown in human cells; replicated across organisms and methods","pmids":["28242692"],"is_preprint":false},{"year":2020,"finding":"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.","method":"C. elegans genetics (double mutants), 3D electron microscopy, fluorescence imaging of NE permeability barrier","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis and imaging in model organism; single lab","pmids":["32271860"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Live-cell imaging, protein biochemistry (co-immunoprecipitation, phospho-mapping), CDK1 phosphorylation site mutagenesis (Ser3/Ser441), mitotic exit imaging assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1-2 — phosphorylation site identified by mutagenesis, interaction changes measured biochemically, spatiotemporal imaging; multiple orthogonal methods in single study","pmids":["34286694"],"is_preprint":false},{"year":2021,"finding":"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.","method":"iPSC-derived neuron model, antisense oligonucleotide knockdown of CHMP7, lentiviral nuclear export inhibition, postmortem tissue immunofluorescence, TDP-43 mRNA expression assays","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function and gain-of-function experiments with defined molecular phenotypes in human neuronal model, replicated in postmortem tissue","pmids":["34321318"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Live-cell imaging, super-resolution microscopy, domain deletion/mutation analysis, co-localization with ER and mitochondrial markers, CHMP7 depletion with mitochondrial division readout","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2-3 — domain mutagenesis with localization and organelle-tethering readouts; single lab","pmids":["35962186"],"is_preprint":false},{"year":2023,"finding":"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.","method":"C. elegans genetics (BAF-1, LEM-2, EMR-1 mutants), fluorescence imaging of NE permeability barrier, domain-specific rescue experiments","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis with multiple alleles and fluorescence readout; single lab","pmids":["37795681"],"is_preprint":false},{"year":2024,"finding":"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.","method":"iPSC-derived neuron model of sALS, co-immunoprecipitation, SUN1 knockdown with CHMP7 localization and NPC injury readouts","journal":"Brain : a journal of neurology","confidence":"Medium","confidence_rationale":"Tier 2-3 — co-IP identifies interaction, knockdown links SUN1 to CHMP7 nuclear accumulation; single lab","pmids":["37639327"],"is_preprint":false},{"year":2024,"finding":"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.","method":"iPSC-derived neuron model of sALS, CHMP2B knockdown with CHMP7 localization and NPC integrity readouts, TDP-43 functional assays","journal":"Acta neuropathologica communications","confidence":"Medium","confidence_rationale":"Tier 2-3 — genetic epistasis (knockdown) in human neuronal model with defined molecular phenotype; single lab","pmids":["39709457"],"is_preprint":false},{"year":2024,"finding":"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.","method":"CRISPR-based microRaft screen (CRaft-ID), immunoprecipitation-mass spectrometry (IP-MS), enhanced CLIP (eCLIP), SmD1 overexpression rescue","journal":"Neuron","confidence":"Medium","confidence_rationale":"Tier 2 — IP-MS and CLIP identify interaction, functional rescue confirms pathway; single lab but multiple orthogonal methods","pmids":["39486415"],"is_preprint":false},{"year":2026,"finding":"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.","method":"siRNA knockdown of CHMP7 and ESCRT components, fluorescence-based telomere integrity assays, genetic interaction analysis (double knockdowns)","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2-3 — genetic epistasis and functional readout in mammalian cells; single lab, novel pathway placement","pmids":["41677621"],"is_preprint":false},{"year":2026,"finding":"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.","method":"shRNA knockdown in primary cortical neurons, RNA-seq transcriptome analysis, immunofluorescence localization during neuronal activity","journal":"Biology","confidence":"Low","confidence_rationale":"Tier 3 — localization and transcriptomic phenotype without direct molecular mechanism; single lab","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 to the ER, enabling recruitment by the inner nuclear membrane protein LEM2 (via direct C-terminal interaction) to sites of nuclear envelope hole closure during mitotic exit and NE rupture repair; CDK1-mediated phosphorylation of CHMP7 at Ser3/Ser441 suppresses LEM2 interaction during M-phase, and spatiotemporal dephosphorylation licenses CHMP7 assembly at telophase to nucleate downstream ESCRT-III (CHMP2A, IST1/CHMP8, CHMP4b) polymerization; in neurons, aberrant nuclear accumulation of CHMP7—promoted by SUN1 and CHMP2B interactions—overactivates NPC surveillance, causing nucleoporin loss and TDP-43 dysfunction relevant to ALS pathogenesis."},"narrative":{"teleology":[{"year":2006,"claim":"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","pmids":["16856878"],"confidence":"Medium","gaps":["No reciprocal co-IP or endogenous interaction validation","Endosomal sorting role based on overexpression phenotypes only","Physiological substrates or cargo not identified"]},{"year":2016,"claim":"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","pmids":["27618263"],"confidence":"High","gaps":["Structural basis of Winged-Helix membrane binding not resolved at atomic level","How CHMP7 transitions from ER-resident to NE-enriched pool was unclear"]},{"year":2017,"claim":"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)","pmids":["28242692"],"confidence":"High","gaps":["Stoichiometry and structural basis of LEM2–CHMP7 complex unknown","Whether additional NE adaptors exist in metazoans was unresolved"]},{"year":2020,"claim":"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","pmids":["32271860"],"confidence":"Medium","gaps":["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"]},{"year":2021,"claim":"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","pmids":["34286694"],"confidence":"High","gaps":["Identity of the phosphatase(s) responsible for CHMP7 dephosphorylation at telophase unknown","Whether additional post-translational modifications regulate CHMP7 activity"]},{"year":2021,"claim":"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","pmids":["34321318"],"confidence":"High","gaps":["What initially triggers CHMP7 nuclear accumulation in disease neurons was unknown","Whether CHMP7-mediated NPC injury is reversible in vivo"]},{"year":2022,"claim":"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","pmids":["35962186"],"confidence":"Medium","gaps":["ESCRT-independent mechanism of ER–mitochondria tethering not molecularly defined","Whether this function is physiologically separable from NE roles in vivo"]},{"year":2023,"claim":"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","pmids":["37795681"],"confidence":"Medium","gaps":["Whether redundancy with BAF-LEM exists in mammalian systems not tested","Nucleoplasmic CHMP7 pool function not molecularly characterized"]},{"year":2024,"claim":"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","pmids":["37639327","39709457"],"confidence":"Medium","gaps":["Direct versus indirect nature of SUN1–CHMP7 interaction not resolved with purified proteins","Whether CHMP2B activates CHMP7 through conformational change or relocalization is unknown"]},{"year":2024,"claim":"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","pmids":["39486415"],"confidence":"Medium","gaps":["Whether CHMP7 RNA-binding is direct or bridged through SmD1 not fully resolved","Mechanism linking splicing defects to CHMP7 relocalization remains indirect"]},{"year":2026,"claim":"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","pmids":["41677621","41744617"],"confidence":"Medium","gaps":["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"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of full-length CHMP7 or CHMP7–LEM2 complex","Phosphatase identity unknown","In vivo therapeutic validation absent"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[1,6]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1,2,6]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1,6]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[1,2,4,7]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5,8,10]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[4]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[1,2,3,4,7]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,8,9]}],"complexes":["ESCRT-III"],"partners":["CHMP4B","LEM2","CHMP2A","IST1","SUN1","CHMP2B","SNRNPD1","AKTIP"],"other_free_text":[]},"mechanistic_narrative":"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]."},"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":157,"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":109,"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":106,"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":59,"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":55,"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":36,"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":27,"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":"27497741","id":"PMC_27497741","title":"Overexpression of CHMP7 from rapeseed and Arabidopsis causes dwarfism and premature senescence in Arabidopsis.","date":"2016","source":"Journal of plant physiology","url":"https://pubmed.ncbi.nlm.nih.gov/27497741","citation_count":10,"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":"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":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":"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":7,"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}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9139,"output_tokens":3621,"usd":0.040866},"stage2":{"model":"claude-opus-4-6","input_tokens":6996,"output_tokens":3140,"usd":0.17022},"total_usd":0.211086,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","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 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.\",\n      \"method\": \"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\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal pulldown with domain mapping, functional VLP assay; single lab\",\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 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.\",\n      \"method\": \"Homology modeling, structure-function analysis with point mutations, live-cell imaging, membrane-binding assays, nuclear envelope reformation assay\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis of defined domain combined with functional rescue and imaging; moderate evidence from single lab with multiple orthogonal methods\",\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. 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.\",\n      \"method\": \"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)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct in vitro binding, genetic epistasis in yeast, and functional knockdown in human cells; replicated across organisms and methods\",\n      \"pmids\": [\"28242692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"C. elegans genetics (double mutants), 3D electron microscopy, fluorescence imaging of NE permeability barrier\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis and imaging in model organism; single lab\",\n      \"pmids\": [\"32271860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Live-cell imaging, protein biochemistry (co-immunoprecipitation, phospho-mapping), CDK1 phosphorylation site mutagenesis (Ser3/Ser441), mitotic exit imaging assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — phosphorylation site identified by mutagenesis, interaction changes measured biochemically, spatiotemporal imaging; multiple orthogonal methods in single study\",\n      \"pmids\": [\"34286694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"iPSC-derived neuron model, antisense oligonucleotide knockdown of CHMP7, lentiviral nuclear export inhibition, postmortem tissue immunofluorescence, TDP-43 mRNA expression assays\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function and gain-of-function experiments with defined molecular phenotypes in human neuronal model, replicated in postmortem tissue\",\n      \"pmids\": [\"34321318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Live-cell imaging, super-resolution microscopy, domain deletion/mutation analysis, co-localization with ER and mitochondrial markers, CHMP7 depletion with mitochondrial division readout\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — domain mutagenesis with localization and organelle-tethering readouts; single lab\",\n      \"pmids\": [\"35962186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"C. elegans genetics (BAF-1, LEM-2, EMR-1 mutants), fluorescence imaging of NE permeability barrier, domain-specific rescue experiments\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with multiple alleles and fluorescence readout; single lab\",\n      \"pmids\": [\"37795681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"iPSC-derived neuron model of sALS, co-immunoprecipitation, SUN1 knockdown with CHMP7 localization and NPC injury readouts\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — co-IP identifies interaction, knockdown links SUN1 to CHMP7 nuclear accumulation; single lab\",\n      \"pmids\": [\"37639327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"iPSC-derived neuron model of sALS, CHMP2B knockdown with CHMP7 localization and NPC integrity readouts, TDP-43 functional assays\",\n      \"journal\": \"Acta neuropathologica communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — genetic epistasis (knockdown) in human neuronal model with defined molecular phenotype; single lab\",\n      \"pmids\": [\"39709457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"CRISPR-based microRaft screen (CRaft-ID), immunoprecipitation-mass spectrometry (IP-MS), enhanced CLIP (eCLIP), SmD1 overexpression rescue\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — IP-MS and CLIP identify interaction, functional rescue confirms pathway; single lab but multiple orthogonal methods\",\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, 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.\",\n      \"method\": \"siRNA knockdown of CHMP7 and ESCRT components, fluorescence-based telomere integrity assays, genetic interaction analysis (double knockdowns)\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — genetic epistasis and functional readout in mammalian cells; single lab, novel pathway placement\",\n      \"pmids\": [\"41677621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"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.\",\n      \"method\": \"shRNA knockdown in primary cortical neurons, RNA-seq transcriptome analysis, immunofluorescence localization during neuronal activity\",\n      \"journal\": \"Biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — localization and transcriptomic phenotype without direct molecular mechanism; single lab\",\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 to the ER, enabling recruitment by the inner nuclear membrane protein LEM2 (via direct C-terminal interaction) to sites of nuclear envelope hole closure during mitotic exit and NE rupture repair; CDK1-mediated phosphorylation of CHMP7 at Ser3/Ser441 suppresses LEM2 interaction during M-phase, and spatiotemporal dephosphorylation licenses CHMP7 assembly at telophase to nucleate downstream ESCRT-III (CHMP2A, IST1/CHMP8, CHMP4b) polymerization; in neurons, aberrant nuclear accumulation of CHMP7—promoted by SUN1 and CHMP2B interactions—overactivates NPC surveillance, causing nucleoporin loss and TDP-43 dysfunction relevant to ALS pathogenesis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"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].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"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.\",\n      \"evidence\": \"Pull-down assays in HEK-293T cells with domain mapping; VLP release and ubiquitinated cargo accumulation assays\",\n      \"pmids\": [\"16856878\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No reciprocal co-IP or endogenous interaction validation\", \"Endosomal sorting role based on overexpression phenotypes only\", \"Physiological substrates or cargo not identified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"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.\",\n      \"evidence\": \"Homology modeling, membrane-binding assays, point mutagenesis with live-cell imaging of NE reformation\",\n      \"pmids\": [\"27618263\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of Winged-Helix membrane binding not resolved at atomic level\", \"How CHMP7 transitions from ER-resident to NE-enriched pool was unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro binding of purified proteins, RNAi knockdown in human cells, S. pombe genetic epistasis (lem2/cmp7 suppression of vps4Δ)\",\n      \"pmids\": [\"28242692\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structural basis of LEM2–CHMP7 complex unknown\", \"Whether additional NE adaptors exist in metazoans was unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"C. elegans double-mutant genetics, 3D electron microscopy, NE permeability assays\",\n      \"pmids\": [\"32271860\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"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.\",\n      \"evidence\": \"Phospho-site mutagenesis, co-IP of phosphomimetic/alanine mutants with LEM2, live-cell imaging of mitotic exit\",\n      \"pmids\": [\"34286694\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the phosphatase(s) responsible for CHMP7 dephosphorylation at telophase unknown\", \"Whether additional post-translational modifications regulate CHMP7 activity\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"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.\",\n      \"evidence\": \"iPSC-derived spinal motor neurons, ASO knockdown and lentiviral nuclear export blockade of CHMP7, postmortem ALS tissue validation\",\n      \"pmids\": [\"34321318\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"What initially triggers CHMP7 nuclear accumulation in disease neurons was unknown\", \"Whether CHMP7-mediated NPC injury is reversible in vivo\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"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.\",\n      \"evidence\": \"Super-resolution microscopy, domain deletion analysis, CHMP7 depletion with mitochondrial division readout\",\n      \"pmids\": [\"35962186\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ESCRT-independent mechanism of ER–mitochondria tethering not molecularly defined\", \"Whether this function is physiologically separable from NE roles in vivo\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"C. elegans genetics with BAF-1, LEM-2, EMR-1 combinatorial mutants; domain-specific rescue; NE permeability imaging\",\n      \"pmids\": [\"37795681\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether redundancy with BAF-LEM exists in mammalian systems not tested\", \"Nucleoplasmic CHMP7 pool function not molecularly characterized\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP of SUN1–CHMP7 and CHMP2B epistasis in iPSC-derived sALS neurons; knockdown rescue of NPC injury and TDP-43 dysfunction\",\n      \"pmids\": [\"37639327\", \"39709457\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect nature of SUN1–CHMP7 interaction not resolved with purified proteins\", \"Whether CHMP2B activates CHMP7 through conformational change or relocalization is unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"evidence\": \"IP-MS, eCLIP, CRaft-ID screen, SmD1 overexpression rescue in ALS iPSC-MNs\",\n      \"pmids\": [\"39486415\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CHMP7 RNA-binding is direct or bridged through SmD1 not fully resolved\", \"Mechanism linking splicing defects to CHMP7 relocalization remains indirect\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"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.\",\n      \"evidence\": \"siRNA double-knockdown epistasis with telomere integrity assays; shRNA knockdown in cortical neurons with RNA-seq and immunofluorescence\",\n      \"pmids\": [\"41677621\", \"41744617\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution structure of full-length CHMP7 or CHMP7–LEM2 complex\", \"Phosphatase identity unknown\", \"In vivo therapeutic validation absent\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [1, 6]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 2, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1, 6]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [1, 2, 4, 7]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5, 8, 10]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [1, 2, 3, 4, 7]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 8, 9]}\n    ],\n    \"complexes\": [\n      \"ESCRT-III\"\n    ],\n    \"partners\": [\n      \"CHMP4B\",\n      \"LEM2\",\n      \"CHMP2A\",\n      \"IST1\",\n      \"SUN1\",\n      \"CHMP2B\",\n      \"SNRNPD1\",\n      \"AKTIP\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}