{"gene":"CHMP1B","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2015,"finding":"CHMP1B and IST1 form a one-start, double-stranded helical copolymer resolved at 4 Å resolution by cryo-EM. The inner strand comprises 'open' CHMP1B subunits that interlock in an elaborate domain-swapped architecture, encircled by an outer strand of 'closed' IST1 subunits. Unlike other ESCRT-III proteins, this CHMP1B/IST1 polymer forms external coats on positively curved membranes in vitro and in vivo, indicating a distinct membrane curvature-sensing and -stabilizing mechanism.","method":"4 Å cryo-EM reconstruction of helical copolymer; in vitro and in vivo membrane-binding assays","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Strong — near-atomic resolution cryo-EM structure with in vitro and in vivo functional validation in a single rigorous study","pmids":["26634441"],"is_preprint":false},{"year":2008,"finding":"The C-terminal tail of CHMP1B binds the MIT domain of spastin through a noncanonical site between the first and third helices of the MIT domain, forming a high-affinity complex (2.5 Å crystal structure). Point mutations in the CHMP1B-binding site of spastin block spastin recruitment to the midbody and impair cytokinesis, establishing CHMP1B as the midbody-targeting signal for spastin.","method":"2.5 Å X-ray crystal structure of CHMP1B C-terminal tail / spastin MIT domain complex; spastin point mutants; fluorescence microscopy of midbody localization; cytokinesis assay","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structure combined with mutagenesis and functional cytokinesis readout","pmids":["18997780"],"is_preprint":false},{"year":2004,"finding":"CHMP1B interacts with spastin via the spastin MIT domain (residues 80–196). Co-immunoprecipitation, in vitro pull-down, beta-lactamase protein fragment complementation, and co-localization in Cos-7 and PC12 cells confirmed the interaction. Expression of CHMP1B prevented the abnormal microtubule phenotype caused by ATPase-defective spastin, indicating CHMP1B functionally modulates spastin activity in membrane trafficking.","method":"Yeast two-hybrid; co-IP; in vitro pull-down; beta-lactamase fragment complementation; immunofluorescence co-localization; dominant-negative spastin phenotype rescue","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Y2H, Co-IP, in vitro pull-down, fragment complementation, phenotypic rescue) in a single study, replicated in multiple cell lines","pmids":["15537668"],"is_preprint":false},{"year":2009,"finding":"CHMP1B forms higher-order helical structures in vitro and interacts with IST1; IST1-CHMP1B interactions are required for cytokinetic abscission. The autoinhibitory alpha5 helix folds back against the ESCRT-III core domain, and its dissociation activates ESCRT-III proteins for membrane assembly.","method":"In vitro helical polymer assembly; biochemical interaction assays; mutagenesis of CHMP3 core-alpha5 interface; abscission functional assay; crystal structures of IST1 and CHMP3 N-terminal core domains","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures plus in vitro assembly and functional abscission assay in one study","pmids":["19525971"],"is_preprint":false},{"year":2005,"finding":"The VPS4A MIT domain binds the C-terminal half of CHMP1B with a Kd of ~20 µM. NMR solution structure of VPS4A MIT domain shows that a conserved leucine (Leu-64) on the third helix, which normally binds a fourth helix in TPR motifs, is used to bind CHMP1B, suggesting ESCRT-III proteins complete the TPR motif.","method":"NMR solution structure; surface plasmon resonance / binding affinity measurement; mutational analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure plus quantitative binding measurement and mutagenesis in a single focused study","pmids":["16174732"],"is_preprint":false},{"year":2006,"finding":"CHMP1B is a direct binding partner of the deubiquitinating enzyme AMSH; VPS4 and AMSH compete for binding to the C-terminal regions of CHMP1B, suggesting coordinated regulation of ESCRT-III disassembly and endosomal cargo deubiquitination.","method":"Co-immunoprecipitation; competitive binding assay between VPS4 and AMSH for CHMP1B C-terminus","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and competition assay, single lab, two orthogonal methods","pmids":["16760479"],"is_preprint":false},{"year":2007,"finding":"The MIT domain of UBPY/USP8 binds CHMP1B (and CHMP1A) among the 11 human CHMP family members. The UBPY MIT domain is essential for endosomal localization and for its functional role in EGF receptor degradation.","method":"Co-immunoprecipitation; UBPY MIT-deletion mutant localization and functional assay; EGFR degradation rescue assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction mapping with deletion mutants and functional rescue, single lab","pmids":["17711858"],"is_preprint":false},{"year":2008,"finding":"LIP5 binds CHMP1B; in CHMP1B (and CHMP2A), the LIP5 binding site encompasses C-terminal sequences that overlap with MIT-interacting motifs (MIMs) used by VPS4, but evidence for a second VPS4-binding site in CHMP1B suggests LIP5 and VPS4 can bind simultaneously. LIP5 preferentially binds polymerized CHMP2A but soluble CHMP5, indicating conformation-dependent regulation.","method":"In vitro binding assays; pull-down with truncation mutants; analysis of MIM overlap","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding with truncation/mutation analysis, single lab, multiple ESCRT-III proteins compared","pmids":["18385515"],"is_preprint":false},{"year":2010,"finding":"C-terminal fragments of CHMP1B (along with other ESCRT-III proteins) activate purified human VPS4A ATPase activity; this activation requires both the MIT-interacting motif and ~50 adjacent amino acids, and mutating VPS4A pore loops alters the response, supporting a model where ESCRT-III proteins thread into the VPS4A pore to stimulate oligomerization and catalysis.","method":"In vitro ATPase activity assay with purified proteins; VPS4A pore-loop mutagenesis; liposome-based oligomerization assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with mutagenesis, single lab","pmids":["20805225"],"is_preprint":false},{"year":2012,"finding":"The first MIT module of the tandem LIP5 MIT domain binds CHMP1B through canonical type 1 MIT-interacting motif (MIM1) interactions. LIP5 can bind MIM1-containing ESCRT-III proteins (including CHMP1B), CHMP5, and VPS4 independently in vitro, but in cells stable VPS4 complex assembly requires LIP5 to simultaneously contact both a MIM1-containing protein and CHMP5.","method":"Solution NMR structure of LIP5-CHMP5 complex; SPR binding measurements; co-immunoprecipitation in cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structure plus SPR quantification plus cellular Co-IP, multiple orthogonal methods in one study","pmids":["23105106"],"is_preprint":false},{"year":2012,"finding":"MITD1 interacts strongly with CHMP1B (and CHMP2A and IST1); CHMP1B and these ESCRT-III subunits are required for recruitment of MITD1 to the midbody, and MITD1 participates in the abscission phase of cytokinesis by negatively regulating IST1-VPS4 interaction.","method":"Co-immunoprecipitation; siRNA knockdown with midbody localization readout; cytokinesis abscission assay","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and functional siRNA knockdown with defined abscission phenotype, single lab","pmids":["23015756"],"is_preprint":false},{"year":2015,"finding":"Crystal structure at 1 Å resolution of the LIP5 N-terminal domain (LIP5NTD) in complex with MIM motifs of both CHMP5 and CHMP1B reveals that ESCRT-III binding induces a conformational change in LIP5NTD via insertion of CHMP5 Tyr182 at the LIP5 core; mutation of Tyr182 partially relieves CHMP5-dependent inhibition of LIP5-mediated VPS4 stimulation.","method":"1 Å X-ray crystal structure; mutagenesis; VPS4 ATPase stimulation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic resolution crystal structure with mutagenesis and functional ATPase assay","pmids":["25637630"],"is_preprint":false},{"year":2018,"finding":"CHMP1B is ubiquitinated within a flexible loop that undergoes conformational changes during polymerization; it is deubiquitinated by USP8/UBPY and found fully devoid of ubiquitin in a ~500 kDa complex containing IST1. EGF stimulation transiently increases ubiquitinated CHMP1B on cell membranes. CHMP1B ubiquitination is required for EGFR trafficking in human cells and wing development in Drosophila.","method":"Ubiquitination assay; co-immunoprecipitation with USP8; size-exclusion chromatography (500 kDa complex); EGF stimulation pulse-chase; Drosophila genetic loss-of-function; EGFR trafficking assay","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (biochemical ubiquitination, Co-IP complex, cell trafficking, Drosophila in vivo genetics) across two organisms","pmids":["29933386"],"is_preprint":false},{"year":2019,"finding":"M1 Spastin recruits ESCRT-III proteins IST1 and CHMP1B to lipid droplets via its MIT domain to facilitate fatty acid trafficking from lipid droplets to peroxisomes. Loss of IST1 or CHMP1B impairs LD-to-peroxisome FA trafficking and lipid peroxidation relief.","method":"Fluorescence live imaging; co-localization; loss-of-function (siRNA/KO); fatty acid trafficking assay; lipid peroxidation assay","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with defined trafficking and lipid peroxidation phenotype plus localization by live imaging, single lab","pmids":["31227594"],"is_preprint":false},{"year":2019,"finding":"HeLa cells lacking CHMP1B (or IST1) develop cellular protrusions, a phenotype also seen in spastin-null cells. The protrusion phenotype requires protrudin and KIF5, placing CHMP1B in the ESCRT-III/spastin axis that limits polarised protrudin-dependent endosomal motility to cell protrusions.","method":"siRNA knockdown in HeLa cells; epistasis with spastin/IST1/protrudin/KIF5 knockdown; fluorescence microscopy of protrusion phenotype; BMP receptor distribution assay","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with multiple knockdowns and defined morphological/trafficking phenotype, single lab","pmids":["31587092"],"is_preprint":false},{"year":2020,"finding":"LZTR1 (a CUL3 ubiquitin ligase adaptor) controls ubiquitination of CHMP1B and thereby regulates dynamics of fusion and fission of recycling endosomes; Noonan syndrome-associated LZTR1 mutations reduce CHMP1B ubiquitination, leading to endosomal accumulation and sustained VEGFR2 signaling.","method":"Co-immunoprecipitation; ubiquitination assay; LZTR1 knockout mouse and endothelial cell knockdown; endosomal trafficking imaging; VEGFR2 signaling readout","journal":"Circulation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, and KO mouse with defined vascular phenotype, single lab","pmids":["32175818"],"is_preprint":false},{"year":2011,"finding":"Calpain-7 binds CHMP1B at its second α-helical region (not the canonical C-terminal MIM1) via its tandem MIT domain (CL7MIT). Coexpression of CHMP1B enhances calpain-7 autolysis, and further coexpression of IST1 forms a ternary calpain-7/CHMP1B/IST1 complex. Overexpression of CHMP1B and IST1 together increases calpain-7 in membrane/organelle fractions.","method":"In vitro pull-down with truncation mutants; co-immunoprecipitation; calpain-7 autolysis assay; subcellular fractionation","journal":"Journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro pull-down combined with Co-IP, functional autolysis assay, and fractionation, single lab","pmids":["21616915"],"is_preprint":false},{"year":2023,"finding":"A small-molecule pseudonatural product that specifically disrupts IST1-CHMP1B interaction inhibits IST1-CHMP1B copolymer formation, blocks transferrin receptor recycling (causing transferrin accumulation in stalled sorting endosomes), and triggers noncanonical LC3 lipidation on stalled endosomes. The compound does not affect cytokinesis, MVB sorting, or extracellular vesicle biogenesis.","method":"Chemical inhibitor screen; Co-IP/interaction assay; transferrin receptor recycling assay; LC3 lipidation assay; cytokinesis and MVB assays as negative controls","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chemical genetic tool with multiple cellular pathway readouts, single lab","pmids":["38635626"],"is_preprint":false},{"year":2023,"finding":"IST1 and CHMP1B together contribute to scission of early endosomal tubular carriers; SNX15 and CHMP1B alternately recruit IST1 to distinct subdomains of sorting endosomes (clathrin subdomain vs. base of endosomal tubules), regulating transferrin receptor and mannose-6-phosphate receptor recycling.","method":"Live-cell microscopy; siRNA depletion; kinetic and spatial trafficking assays for transferrin receptor and M6PR; co-localization with endosomal markers","journal":"Traffic (Copenhagen, Denmark)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live-cell imaging with siRNA knockdown and multiple cargo tracking readouts, single lab","pmids":["37926552"],"is_preprint":false},{"year":2023,"finding":"CHMP1B exhibited nuclear localization in mammalian cells and recruited both human and Asgard VPS4 to nuclear foci; mutation of the ESCRT-III N-terminal region abolished these nuclear properties, indicating the N-terminal domain mediates nuclear targeting and chromatin association.","method":"Fluorescence microscopy of nuclear localization; mutagenesis of N-terminal region; interspecies VPS4 recruitment assay","journal":"The ISME journal","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, fluorescence microscopy with mutagenesis but no structural or biochemical chromatin-binding validation","pmids":["36221007"],"is_preprint":false},{"year":2023,"finding":"Cryo-EM of brominated lipids within CHMP1B/IST1-coated membrane nanotubes revealed leaflet-level structural asymmetries: constricted membranes show altered lipid diffusion, leaflet thinning, lipid compositional/conformational asymmetry, and two CHMP1B phenylalanine residues create a helical hydrophobic defect on the outer leaflet where polyunsaturated docosahexaenoyl tails accumulate.","method":"Cryo-EM with brominated lipid contrast probes; molecular dynamics simulation; reconstituted CHMP1B/IST1 nanotubes","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM with novel lipid probes plus MD simulation on reconstituted CHMP1B/IST1 system","pmids":["36624348"],"is_preprint":false},{"year":2022,"finding":"HCV infection enhances the interaction between CHMP1B and VPS4A (but not VPS4B) via HCV-induced polyubiquitylation of VPS4A at K23 and K121; VPS4A K23R/K121R mutant fails to interact with CHMP1B and has reduced ATPase activity, indicating that VPS4A ubiquitylation promotes CHMP1B binding and VPS4A activation for HCV particle release.","method":"Co-immunoprecipitation; site-directed mutagenesis (VPS4A K23R/K121R); ATPase activity assay; siRNA knockdown; viral infectivity titer","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with mutagenesis and ATPase assay, single lab","pmids":["35044214"],"is_preprint":false},{"year":2025,"finding":"CHMP2A knockout reveals an ordered, hierarchical assembly of ESCRT-III at the cytokinetic abscission site: IST1 and CHMP2B are minimally disrupted, while CHMP1B (along with CHMP4B and CHMP3) shows progressively severe mislocalization, establishing CHMP2A as an upstream organizer required for correct CHMP1B positioning during abscission.","method":"CHMP2A knockout; live-cell imaging; structured illumination microscopy (SIM); correlative light-electron microscopy; dual-protein imaging of ESCRT-III subunits","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with multiple imaging modalities and epistatic ordering of subunits, single lab","pmids":["40928930"],"is_preprint":false},{"year":2022,"finding":"Conserved leucine residues L192 and L195 within the MIM (MIT-interacting motif) domain of CHMP1B are required for interaction with USP8/UBPY, whereas the ubiquitination status of CHMP1B does not affect this interaction; deletion of the MIM domain abolishes binding.","method":"HTRF interaction assay; CHMP1B point-mutant and deletion analysis (L192A/L195A and MIM deletion); comparison of ubiquitin-deficient CHMP1B mutant (4K→R) vs wild-type binding to USP8","journal":"SLAS discovery : advancing life sciences R & D","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative interaction assay with multiple CHMP1B mutants, single lab","pmids":["35995394"],"is_preprint":false},{"year":2011,"finding":"Calpain-7 N-terminal tandem MIT domain directly interacts with CHMP1B; the interaction was confirmed by pulldown assay using recombinant proteins. Overexpression of GFP-CHMPs or dominant-negative VPS4B caused calpain-7 accumulation in perinuclear puncta overlapping with endocytosed EGF, and endogenous calpain-7 partitions largely to cytosol with a small fraction in particulate fractions.","method":"Strep-tag pulldown from stable HEK293T transfectants; recombinant protein pulldown; fluorescence microscopy; subcellular fractionation","journal":"Journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct recombinant protein pulldown plus subcellular fractionation, single lab","pmids":["18316332"],"is_preprint":false},{"year":2023,"finding":"CHMP1B (along with CHMP1A, CHMP5, and IST1 as accessory ESCRT-III proteins) is required for intraluminal vesicle formation in Drosophila recycling endosomes but, unlike core ESCRTs, is not involved in degradation of ubiquitinated proteins in late endosomes, revealing a specific ubiquitin-independent role in Rab11a-exosome generation.","method":"Drosophila genetic knockdown; comparative proteomics of Rab11a-enriched vs. total exosome preparations; CHMP5 siRNA knockdown in HCT116 cells; ILV formation assay","journal":"Journal of extracellular vesicles","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo Drosophila genetics plus human cell knockdown with defined vesicle biogenesis readout, single lab","pmids":["36872252"],"is_preprint":false}],"current_model":"CHMP1B is an ESCRT-III subunit that, together with IST1, forms a double-stranded helical copolymer that coats positively curved membranes to drive normal-topology membrane scission events including cytokinetic abscission, early endosomal tubule scission, and fatty acid transfer at lipid droplet–peroxisome contacts; its C-terminal MIM1 motif mediates high-affinity binding to MIT-domain proteins (spastin, VPS4, LIP5, UBPY/USP8, AMSH, MITD1, calpain-7), recruiting them to their sites of action, while dynamic ubiquitination of CHMP1B—written by LZTR1-CUL3 and erased by USP8—regulates its membrane recruitment and ESCRT-III polymer assembly in response to EGF signaling and endosomal repair."},"narrative":{"mechanistic_narrative":"CHMP1B is an ESCRT-III subunit that, with IST1, builds a one-start double-stranded helical copolymer in which 'open' interlocked CHMP1B subunits form the inner strand and 'closed' IST1 subunits form the outer strand, an arrangement that uniquely coats positively curved membranes and thereby drives normal-topology membrane remodeling events [PMID:26634441]. Activation of CHMP1B for assembly involves release of an autoinhibitory α5 helix from the ESCRT-III core, and the resulting IST1–CHMP1B interaction is required for cytokinetic abscission [PMID:19525971]. At constricted membranes the copolymer imposes leaflet-level lipid asymmetry, with two CHMP1B phenylalanines creating a helical hydrophobic defect on the outer leaflet that recruits polyunsaturated lipid tails [PMID:36624348]. CHMP1B performs scission across multiple normal-topology sites: it scissions early endosomal tubular carriers to recycle transferrin and mannose-6-phosphate receptors, with SNX15 and CHMP1B alternately recruiting IST1 to distinct endosomal subdomains [PMID:37926552, PMID:38635626], and is recruited by spastin to lipid droplets to support fatty acid transfer to peroxisomes [PMID:31227594]. Its C-terminal MIM1 motif is a high-affinity docking site for MIT-domain proteins, including spastin—for which CHMP1B is the midbody-targeting signal [PMID:18997780, PMID:15537668]—VPS4A, whose ATPase it stimulates [PMID:16174732, PMID:20805225], LIP5 [PMID:23105106, PMID:25637630], the deubiquitinases AMSH and UBPY/USP8 [PMID:16760479, PMID:17711858, PMID:35995394], and MITD1 [PMID:23015756], while calpain-7 binds a noncanonical second α-helical region [PMID:21616915, PMID:18316332]. CHMP1B is itself dynamically ubiquitinated within a polymerization-sensitive loop—written by the LZTR1-CUL3 ligase and erased by USP8—and this modification governs its membrane recruitment and ESCRT-III assembly during EGF and VEGFR2 receptor trafficking; LZTR1 mutations that reduce CHMP1B ubiquitination cause endosomal accumulation and sustained VEGFR2 signaling in the context of Noonan syndrome [PMID:29933386, PMID:32175818, PMID:35995394]. ESCRT-III subunit order also constrains CHMP1B function, as CHMP2A acts upstream to position CHMP1B correctly at the abscission site [PMID:40928930].","teleology":[{"year":2004,"claim":"Established the first functional partner of CHMP1B by showing it binds and modulates the microtubule-severing ATPase spastin, linking an ESCRT-III protein to membrane trafficking and microtubule regulation.","evidence":"Yeast two-hybrid, Co-IP, in vitro pull-down, fragment complementation and dominant-negative spastin rescue in Cos-7/PC12 cells","pmids":["15537668"],"confidence":"High","gaps":["Structural basis of the interaction not yet resolved","Did not define the spastin recruitment site or in vivo cytokinesis role"]},{"year":2005,"claim":"Defined the molecular logic of MIT-domain recognition by showing the VPS4A MIT domain binds the CHMP1B C-terminus with a conserved leucine, framing ESCRT-III tails as TPR-completing ligands.","evidence":"NMR solution structure of VPS4A MIT domain, SPR affinity measurement and mutagenesis","pmids":["16174732"],"confidence":"High","gaps":["Modest ~20 µM affinity leaves cellular avidity contributors undefined","Did not address how binding triggers VPS4 disassembly activity"]},{"year":2006,"claim":"Showed that VPS4 and the deubiquitinase AMSH compete for the CHMP1B C-terminus, suggesting coordinated control of ESCRT-III disassembly and cargo deubiquitination.","evidence":"Co-IP and competitive binding assay","pmids":["16760479"],"confidence":"Medium","gaps":["Single lab, no structure of the competitive interface","Functional consequence of competition not directly tested"]},{"year":2007,"claim":"Identified UBPY/USP8 as a CHMP1B-binding deubiquitinase whose MIT domain is required for endosomal localization and EGFR degradation, placing CHMP1B in receptor downregulation.","evidence":"Co-IP, UBPY MIT-deletion localization and EGFR degradation rescue","pmids":["17711858"],"confidence":"Medium","gaps":["Did not map the CHMP1B residues required for binding","Direct role of CHMP1B (vs CHMP1A) in EGFR degradation not isolated"]},{"year":2008,"claim":"Resolved the structural basis for CHMP1B as the midbody-targeting signal for spastin and mapped overlapping LIP5/VPS4 binding regions on the CHMP1B C-terminus.","evidence":"2.5 Å crystal structure of CHMP1B tail/spastin MIT, spastin point mutants and cytokinesis assays; separate in vitro LIP5 binding/truncation analysis","pmids":["18997780","18385515"],"confidence":"High","gaps":["Whether a true second VPS4 site exists on CHMP1B remained inferential","Conformational dependence of LIP5 binding only partially defined"]},{"year":2009,"claim":"Demonstrated that CHMP1B autoinhibition by the α5 helix gates polymerization and that IST1–CHMP1B assembly is required for abscission, establishing the activation switch for this copolymer.","evidence":"In vitro helical assembly, core-α5 interface mutagenesis, abscission assay and crystal structures of IST1/CHMP3 cores","pmids":["19525971"],"confidence":"High","gaps":["Trigger that releases autoinhibition in vivo not identified","Copolymer architecture not yet resolved"]},{"year":2010,"claim":"Provided a mechanistic model for how CHMP1B activates VPS4A, showing its C-terminal fragment threads into the VPS4A pore to stimulate ATPase activity.","evidence":"In vitro ATPase assays with purified proteins, VPS4A pore-loop mutagenesis and liposome oligomerization","pmids":["20805225"],"confidence":"Medium","gaps":["Single lab reconstitution without structure of the threaded state","Relevance to full-length polymerized CHMP1B not tested"]},{"year":2011,"claim":"Identified calpain-7 as a noncanonical CHMP1B partner binding a second α-helical region, and showed CHMP1B/IST1 form a ternary complex regulating calpain-7 autolysis and membrane partitioning.","evidence":"Recombinant pull-down with truncation mutants, Co-IP, autolysis assay and subcellular fractionation","pmids":["21616915","18316332"],"confidence":"Medium","gaps":["Physiological substrate of calpain-7 at ESCRT sites unknown","Single lab, no structure of the noncanonical interface"]},{"year":2012,"claim":"Refined LIP5 and MITD1 recognition of CHMP1B, showing LIP5 uses canonical MIM1 contacts but requires simultaneous CHMP5 binding to assemble stable VPS4 complexes, while MITD1 is recruited to the midbody by CHMP1B to regulate IST1-VPS4.","evidence":"NMR structures, SPR, cellular Co-IP (LIP5); Co-IP and siRNA abscission assays (MITD1)","pmids":["23105106","23015756"],"confidence":"High","gaps":["How these competing adaptors are temporally ordered at one site unclear","MITD1 study was single-lab Medium confidence"]},{"year":2015,"claim":"Delivered the atomic architecture of the CHMP1B/IST1 copolymer and an atomic-resolution LIP5–CHMP1B/CHMP5 structure, revealing a unique positive-curvature external coat and the conformational coupling of ESCRT-III binding to LIP5/VPS4 stimulation.","evidence":"4 Å cryo-EM of the copolymer plus membrane assays; 1 Å crystal structure of LIP5NTD with CHMP5/CHMP1B MIMs and ATPase assay","pmids":["26634441","25637630"],"confidence":"High","gaps":["In vivo membrane substrates of the external coat not yet enumerated","How curvature sensing selects sites in cells unresolved"]},{"year":2018,"claim":"Established dynamic ubiquitination of CHMP1B—erased by USP8 within a polymerization-sensitive loop—as a regulatory switch for membrane recruitment and EGFR trafficking conserved into Drosophila.","evidence":"Ubiquitination assays, USP8 Co-IP, size-exclusion of a 500 kDa IST1 complex, EGF pulse-chase and Drosophila loss-of-function","pmids":["29933386"],"confidence":"High","gaps":["The ligase writing the modification was not yet identified","Quantitative stoichiometry of ubiquitin on polymer vs soluble CHMP1B unclear"]},{"year":2019,"claim":"Extended CHMP1B function to interorganelle lipid transfer and to endosomal motility control, showing spastin recruits CHMP1B/IST1 to lipid droplets for fatty acid trafficking and that loss of CHMP1B produces protrudin/KIF5-dependent protrusions.","evidence":"Live imaging, loss-of-function, fatty acid trafficking and peroxidation assays; siRNA epistasis with spastin/protrudin/KIF5 and BMP receptor distribution","pmids":["31227594","31587092"],"confidence":"Medium","gaps":["Whether scission per se mediates FA transfer not directly proven","Both single-lab studies without structural correlates"]},{"year":2020,"claim":"Identified the LZTR1-CUL3 ligase as the writer of CHMP1B ubiquitination controlling recycling-endosome dynamics, and linked Noonan-syndrome LZTR1 mutations to reduced CHMP1B ubiquitination, endosomal accumulation and sustained VEGFR2 signaling.","evidence":"Co-IP, ubiquitination assays, LZTR1 knockout mouse and endothelial knockdown with trafficking imaging and VEGFR2 readout","pmids":["32175818"],"confidence":"Medium","gaps":["Direct ubiquitination sites and chain type on CHMP1B by LZTR1 not mapped","Single lab; vascular phenotype mechanism partly correlative"]},{"year":2022,"claim":"Refined CHMP1B–USP8 recognition to specific MIM leucines independent of ubiquitin status, and showed pathogen and host ubiquitin signals on VPS4A tune CHMP1B engagement.","evidence":"HTRF with CHMP1B L192A/L195A and MIM-deletion mutants (USP8); HCV-induced VPS4A K23/K121 ubiquitylation, Co-IP, ATPase and infectivity assays","pmids":["35995394","35044214"],"confidence":"Medium","gaps":["Whether USP8 recognition mode differs across MIT proteins not resolved","Generality of VPS4A ubiquitin-gated CHMP1B binding beyond HCV unknown"]},{"year":2023,"claim":"Defined the membrane-physical mechanism and the cargo-specific, ubiquitin-independent scission roles of the CHMP1B/IST1 copolymer at endosomes and exosomes, with a chemical tool isolating the recycling function from cytokinesis and MVB sorting.","evidence":"Cryo-EM of brominated lipids plus MD; live-imaging siRNA of SNX15/CHMP1B endosomal subdomains; small-molecule IST1-CHMP1B disruptor with transferrin recycling and LC3 readouts; Drosophila/HCT116 Rab11a-exosome ILV assays","pmids":["36624348","37926552","38635626","36872252"],"confidence":"Medium","gaps":["How distinct subdomain recruitment cues (SNX15 vs CHMP1B) are coordinated unclear","Trigger for noncanonical LC3 lipidation on stalled endosomes undefined"]},{"year":2023,"claim":"Reported a nuclear/chromatin-associated property of CHMP1B mediated by its N-terminal region, raising a possible role outside membrane scission.","evidence":"Fluorescence microscopy of nuclear foci, N-terminal mutagenesis and interspecies VPS4 recruitment","pmids":["36221007"],"confidence":"Low","gaps":["No biochemical or structural validation of chromatin binding","Functional consequence of nuclear localization untested","Single lab, not independently confirmed"]},{"year":2025,"claim":"Established that CHMP1B positioning at the abscission site is hierarchically controlled, with CHMP2A acting upstream to organize correct CHMP1B localization.","evidence":"CHMP2A knockout with live imaging, SIM and correlative light-electron microscopy of ESCRT-III subunits","pmids":["40928930"],"confidence":"Medium","gaps":["Molecular interface by which CHMP2A directs CHMP1B not defined","Whether the same hierarchy operates at endosomes unknown"]},{"year":null,"claim":"How the various competing MIT-domain effectors and the ubiquitination cycle are temporally choreographed to select among CHMP1B's distinct scission sites (abscission, endosomal tubules, lipid-droplet contacts, exosome biogenesis) remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified in vivo model coupling ubiquitination state to site selection","Site-specific determinants distinguishing normal-topology scission contexts undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,3,20]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[20]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,8,11]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,2,10]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,12]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[6,18,25]},{"term_id":"GO:0005811","term_label":"lipid droplet","supporting_discovery_ids":[13]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[12,24]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1,3,10,22]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[13,14,18,25]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[12,15]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[6,17,18]}],"complexes":["CHMP1B-IST1 ESCRT-III copolymer","ESCRT-III","calpain-7/CHMP1B/IST1 ternary complex"],"partners":["IST1","SPAST","VPS4A","LIP5","USP8","AMSH","MITD1","CAPN7"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q7LBR1","full_name":"Charged multivesicular body protein 1b","aliases":["CHMP1.5","Chromatin-modifying protein 1b","CHMP1b","Vacuolar protein sorting-associated protein 46-2","Vps46-2","hVps46-2"],"length_aa":199,"mass_kda":22.1,"function":"Probable peripherally associated component of the endosomal sorting required for transport complex III (ESCRT-III) which is involved in multivesicular bodies (MVBs) formation and sorting of endosomal cargo proteins into MVBs. MVBs contain intraluminal vesicles (ILVs) that are generated by invagination and scission from the limiting membrane of the endosome and mostly are delivered to lysosomes enabling degradation of membrane proteins, such as stimulated growth factor receptors, lysosomal enzymes and lipids. The MVB pathway appears to require the sequential function of ESCRT-O, -I,-II and -III complexes. ESCRT-III proteins mostly dissociate from the invaginating membrane before the ILV is released. The ESCRT machinery also functions in topologically equivalent membrane fission events, such as the terminal stages of cytokinesis and the budding of enveloped viruses (HIV-1 and other lentiviruses). ESCRT-III proteins are believed to mediate the necessary vesicle extrusion and/or membrane fission activities, possibly in conjunction with the AAA ATPase VPS4. Involved in cytokinesis. Involved in recruiting VPS4A and/or VPS4B and SPAST to the midbody of dividing cells. Involved in HIV-1 p6- and p9-dependent virus release","subcellular_location":"Cytoplasm, cytosol; Endosome; Late endosome membrane","url":"https://www.uniprot.org/uniprotkb/Q7LBR1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CHMP1B","classification":"Not Classified","n_dependent_lines":8,"n_total_lines":1208,"dependency_fraction":0.006622516556291391},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CHMP1B","total_profiled":1310},"omim":[{"mim_id":"621486","title":"MICROTUBULE-INTERACTING AND TRAFFICKING DOMAIN-CONTAINING PROTEIN 1; MITD1","url":"https://www.omim.org/entry/621486"},{"mim_id":"616434","title":"IST1 FACTOR ASSOCIATED WITH ESCRT-III; IST1","url":"https://www.omim.org/entry/616434"},{"mim_id":"609983","title":"VACUOLAR PROTEIN SORTING 4 HOMOLOG B; VPS4B","url":"https://www.omim.org/entry/609983"},{"mim_id":"609982","title":"VACUOLAR PROTEIN SORTING 4 HOMOLOG A; VPS4A","url":"https://www.omim.org/entry/609982"},{"mim_id":"606486","title":"CHARGED MULTIVESICULAR BODY PROTEIN 1B; CHMP1B","url":"https://www.omim.org/entry/606486"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Midbody","reliability":"Approved"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":344.7}],"url":"https://www.proteinatlas.org/search/CHMP1B"},"hgnc":{"alias_symbol":["CHMP1.5","C18orf2","Vps46B"],"prev_symbol":[]},"alphafold":{"accession":"Q7LBR1","domains":[{"cath_id":"-","chopping":"106-160","consensus_level":"medium","plddt":75.6022,"start":106,"end":160},{"cath_id":"1.10.287","chopping":"1-104","consensus_level":"medium","plddt":91.8639,"start":1,"end":104}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7LBR1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q7LBR1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q7LBR1-F1-predicted_aligned_error_v6.png","plddt_mean":80.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CHMP1B","jax_strain_url":"https://www.jax.org/strain/search?query=CHMP1B"},"sequence":{"accession":"Q7LBR1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q7LBR1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q7LBR1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7LBR1"}},"corpus_meta":[{"pmid":"17239033","id":"PMC_17239033","title":"Molecular 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The inner strand comprises 'open' CHMP1B subunits that interlock in an elaborate domain-swapped architecture, encircled by an outer strand of 'closed' IST1 subunits. Unlike other ESCRT-III proteins, this CHMP1B/IST1 polymer forms external coats on positively curved membranes in vitro and in vivo, indicating a distinct membrane curvature-sensing and -stabilizing mechanism.\",\n      \"method\": \"4 Å cryo-EM reconstruction of helical copolymer; in vitro and in vivo membrane-binding assays\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — near-atomic resolution cryo-EM structure with in vitro and in vivo functional validation in a single rigorous study\",\n      \"pmids\": [\"26634441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The C-terminal tail of CHMP1B binds the MIT domain of spastin through a noncanonical site between the first and third helices of the MIT domain, forming a high-affinity complex (2.5 Å crystal structure). Point mutations in the CHMP1B-binding site of spastin block spastin recruitment to the midbody and impair cytokinesis, establishing CHMP1B as the midbody-targeting signal for spastin.\",\n      \"method\": \"2.5 Å X-ray crystal structure of CHMP1B C-terminal tail / spastin MIT domain complex; spastin point mutants; fluorescence microscopy of midbody localization; cytokinesis assay\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structure combined with mutagenesis and functional cytokinesis readout\",\n      \"pmids\": [\"18997780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CHMP1B interacts with spastin via the spastin MIT domain (residues 80–196). Co-immunoprecipitation, in vitro pull-down, beta-lactamase protein fragment complementation, and co-localization in Cos-7 and PC12 cells confirmed the interaction. Expression of CHMP1B prevented the abnormal microtubule phenotype caused by ATPase-defective spastin, indicating CHMP1B functionally modulates spastin activity in membrane trafficking.\",\n      \"method\": \"Yeast two-hybrid; co-IP; in vitro pull-down; beta-lactamase fragment complementation; immunofluorescence co-localization; dominant-negative spastin phenotype rescue\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Y2H, Co-IP, in vitro pull-down, fragment complementation, phenotypic rescue) in a single study, replicated in multiple cell lines\",\n      \"pmids\": [\"15537668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CHMP1B forms higher-order helical structures in vitro and interacts with IST1; IST1-CHMP1B interactions are required for cytokinetic abscission. The autoinhibitory alpha5 helix folds back against the ESCRT-III core domain, and its dissociation activates ESCRT-III proteins for membrane assembly.\",\n      \"method\": \"In vitro helical polymer assembly; biochemical interaction assays; mutagenesis of CHMP3 core-alpha5 interface; abscission functional assay; crystal structures of IST1 and CHMP3 N-terminal core domains\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures plus in vitro assembly and functional abscission assay in one study\",\n      \"pmids\": [\"19525971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The VPS4A MIT domain binds the C-terminal half of CHMP1B with a Kd of ~20 µM. NMR solution structure of VPS4A MIT domain shows that a conserved leucine (Leu-64) on the third helix, which normally binds a fourth helix in TPR motifs, is used to bind CHMP1B, suggesting ESCRT-III proteins complete the TPR motif.\",\n      \"method\": \"NMR solution structure; surface plasmon resonance / binding affinity measurement; mutational analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure plus quantitative binding measurement and mutagenesis in a single focused study\",\n      \"pmids\": [\"16174732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CHMP1B is a direct binding partner of the deubiquitinating enzyme AMSH; VPS4 and AMSH compete for binding to the C-terminal regions of CHMP1B, suggesting coordinated regulation of ESCRT-III disassembly and endosomal cargo deubiquitination.\",\n      \"method\": \"Co-immunoprecipitation; competitive binding assay between VPS4 and AMSH for CHMP1B C-terminus\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and competition assay, single lab, two orthogonal methods\",\n      \"pmids\": [\"16760479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The MIT domain of UBPY/USP8 binds CHMP1B (and CHMP1A) among the 11 human CHMP family members. The UBPY MIT domain is essential for endosomal localization and for its functional role in EGF receptor degradation.\",\n      \"method\": \"Co-immunoprecipitation; UBPY MIT-deletion mutant localization and functional assay; EGFR degradation rescue assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction mapping with deletion mutants and functional rescue, single lab\",\n      \"pmids\": [\"17711858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"LIP5 binds CHMP1B; in CHMP1B (and CHMP2A), the LIP5 binding site encompasses C-terminal sequences that overlap with MIT-interacting motifs (MIMs) used by VPS4, but evidence for a second VPS4-binding site in CHMP1B suggests LIP5 and VPS4 can bind simultaneously. LIP5 preferentially binds polymerized CHMP2A but soluble CHMP5, indicating conformation-dependent regulation.\",\n      \"method\": \"In vitro binding assays; pull-down with truncation mutants; analysis of MIM overlap\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding with truncation/mutation analysis, single lab, multiple ESCRT-III proteins compared\",\n      \"pmids\": [\"18385515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"C-terminal fragments of CHMP1B (along with other ESCRT-III proteins) activate purified human VPS4A ATPase activity; this activation requires both the MIT-interacting motif and ~50 adjacent amino acids, and mutating VPS4A pore loops alters the response, supporting a model where ESCRT-III proteins thread into the VPS4A pore to stimulate oligomerization and catalysis.\",\n      \"method\": \"In vitro ATPase activity assay with purified proteins; VPS4A pore-loop mutagenesis; liposome-based oligomerization assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with mutagenesis, single lab\",\n      \"pmids\": [\"20805225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The first MIT module of the tandem LIP5 MIT domain binds CHMP1B through canonical type 1 MIT-interacting motif (MIM1) interactions. LIP5 can bind MIM1-containing ESCRT-III proteins (including CHMP1B), CHMP5, and VPS4 independently in vitro, but in cells stable VPS4 complex assembly requires LIP5 to simultaneously contact both a MIM1-containing protein and CHMP5.\",\n      \"method\": \"Solution NMR structure of LIP5-CHMP5 complex; SPR binding measurements; co-immunoprecipitation in cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structure plus SPR quantification plus cellular Co-IP, multiple orthogonal methods in one study\",\n      \"pmids\": [\"23105106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MITD1 interacts strongly with CHMP1B (and CHMP2A and IST1); CHMP1B and these ESCRT-III subunits are required for recruitment of MITD1 to the midbody, and MITD1 participates in the abscission phase of cytokinesis by negatively regulating IST1-VPS4 interaction.\",\n      \"method\": \"Co-immunoprecipitation; siRNA knockdown with midbody localization readout; cytokinesis abscission assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and functional siRNA knockdown with defined abscission phenotype, single lab\",\n      \"pmids\": [\"23015756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structure at 1 Å resolution of the LIP5 N-terminal domain (LIP5NTD) in complex with MIM motifs of both CHMP5 and CHMP1B reveals that ESCRT-III binding induces a conformational change in LIP5NTD via insertion of CHMP5 Tyr182 at the LIP5 core; mutation of Tyr182 partially relieves CHMP5-dependent inhibition of LIP5-mediated VPS4 stimulation.\",\n      \"method\": \"1 Å X-ray crystal structure; mutagenesis; VPS4 ATPase stimulation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic resolution crystal structure with mutagenesis and functional ATPase assay\",\n      \"pmids\": [\"25637630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CHMP1B is ubiquitinated within a flexible loop that undergoes conformational changes during polymerization; it is deubiquitinated by USP8/UBPY and found fully devoid of ubiquitin in a ~500 kDa complex containing IST1. EGF stimulation transiently increases ubiquitinated CHMP1B on cell membranes. CHMP1B ubiquitination is required for EGFR trafficking in human cells and wing development in Drosophila.\",\n      \"method\": \"Ubiquitination assay; co-immunoprecipitation with USP8; size-exclusion chromatography (500 kDa complex); EGF stimulation pulse-chase; Drosophila genetic loss-of-function; EGFR trafficking assay\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (biochemical ubiquitination, Co-IP complex, cell trafficking, Drosophila in vivo genetics) across two organisms\",\n      \"pmids\": [\"29933386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"M1 Spastin recruits ESCRT-III proteins IST1 and CHMP1B to lipid droplets via its MIT domain to facilitate fatty acid trafficking from lipid droplets to peroxisomes. Loss of IST1 or CHMP1B impairs LD-to-peroxisome FA trafficking and lipid peroxidation relief.\",\n      \"method\": \"Fluorescence live imaging; co-localization; loss-of-function (siRNA/KO); fatty acid trafficking assay; lipid peroxidation assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with defined trafficking and lipid peroxidation phenotype plus localization by live imaging, single lab\",\n      \"pmids\": [\"31227594\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HeLa cells lacking CHMP1B (or IST1) develop cellular protrusions, a phenotype also seen in spastin-null cells. The protrusion phenotype requires protrudin and KIF5, placing CHMP1B in the ESCRT-III/spastin axis that limits polarised protrudin-dependent endosomal motility to cell protrusions.\",\n      \"method\": \"siRNA knockdown in HeLa cells; epistasis with spastin/IST1/protrudin/KIF5 knockdown; fluorescence microscopy of protrusion phenotype; BMP receptor distribution assay\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with multiple knockdowns and defined morphological/trafficking phenotype, single lab\",\n      \"pmids\": [\"31587092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LZTR1 (a CUL3 ubiquitin ligase adaptor) controls ubiquitination of CHMP1B and thereby regulates dynamics of fusion and fission of recycling endosomes; Noonan syndrome-associated LZTR1 mutations reduce CHMP1B ubiquitination, leading to endosomal accumulation and sustained VEGFR2 signaling.\",\n      \"method\": \"Co-immunoprecipitation; ubiquitination assay; LZTR1 knockout mouse and endothelial cell knockdown; endosomal trafficking imaging; VEGFR2 signaling readout\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, and KO mouse with defined vascular phenotype, single lab\",\n      \"pmids\": [\"32175818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Calpain-7 binds CHMP1B at its second α-helical region (not the canonical C-terminal MIM1) via its tandem MIT domain (CL7MIT). Coexpression of CHMP1B enhances calpain-7 autolysis, and further coexpression of IST1 forms a ternary calpain-7/CHMP1B/IST1 complex. Overexpression of CHMP1B and IST1 together increases calpain-7 in membrane/organelle fractions.\",\n      \"method\": \"In vitro pull-down with truncation mutants; co-immunoprecipitation; calpain-7 autolysis assay; subcellular fractionation\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro pull-down combined with Co-IP, functional autolysis assay, and fractionation, single lab\",\n      \"pmids\": [\"21616915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A small-molecule pseudonatural product that specifically disrupts IST1-CHMP1B interaction inhibits IST1-CHMP1B copolymer formation, blocks transferrin receptor recycling (causing transferrin accumulation in stalled sorting endosomes), and triggers noncanonical LC3 lipidation on stalled endosomes. The compound does not affect cytokinesis, MVB sorting, or extracellular vesicle biogenesis.\",\n      \"method\": \"Chemical inhibitor screen; Co-IP/interaction assay; transferrin receptor recycling assay; LC3 lipidation assay; cytokinesis and MVB assays as negative controls\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chemical genetic tool with multiple cellular pathway readouts, single lab\",\n      \"pmids\": [\"38635626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IST1 and CHMP1B together contribute to scission of early endosomal tubular carriers; SNX15 and CHMP1B alternately recruit IST1 to distinct subdomains of sorting endosomes (clathrin subdomain vs. base of endosomal tubules), regulating transferrin receptor and mannose-6-phosphate receptor recycling.\",\n      \"method\": \"Live-cell microscopy; siRNA depletion; kinetic and spatial trafficking assays for transferrin receptor and M6PR; co-localization with endosomal markers\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live-cell imaging with siRNA knockdown and multiple cargo tracking readouts, single lab\",\n      \"pmids\": [\"37926552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CHMP1B exhibited nuclear localization in mammalian cells and recruited both human and Asgard VPS4 to nuclear foci; mutation of the ESCRT-III N-terminal region abolished these nuclear properties, indicating the N-terminal domain mediates nuclear targeting and chromatin association.\",\n      \"method\": \"Fluorescence microscopy of nuclear localization; mutagenesis of N-terminal region; interspecies VPS4 recruitment assay\",\n      \"journal\": \"The ISME journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, fluorescence microscopy with mutagenesis but no structural or biochemical chromatin-binding validation\",\n      \"pmids\": [\"36221007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cryo-EM of brominated lipids within CHMP1B/IST1-coated membrane nanotubes revealed leaflet-level structural asymmetries: constricted membranes show altered lipid diffusion, leaflet thinning, lipid compositional/conformational asymmetry, and two CHMP1B phenylalanine residues create a helical hydrophobic defect on the outer leaflet where polyunsaturated docosahexaenoyl tails accumulate.\",\n      \"method\": \"Cryo-EM with brominated lipid contrast probes; molecular dynamics simulation; reconstituted CHMP1B/IST1 nanotubes\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM with novel lipid probes plus MD simulation on reconstituted CHMP1B/IST1 system\",\n      \"pmids\": [\"36624348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HCV infection enhances the interaction between CHMP1B and VPS4A (but not VPS4B) via HCV-induced polyubiquitylation of VPS4A at K23 and K121; VPS4A K23R/K121R mutant fails to interact with CHMP1B and has reduced ATPase activity, indicating that VPS4A ubiquitylation promotes CHMP1B binding and VPS4A activation for HCV particle release.\",\n      \"method\": \"Co-immunoprecipitation; site-directed mutagenesis (VPS4A K23R/K121R); ATPase activity assay; siRNA knockdown; viral infectivity titer\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with mutagenesis and ATPase assay, single lab\",\n      \"pmids\": [\"35044214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CHMP2A knockout reveals an ordered, hierarchical assembly of ESCRT-III at the cytokinetic abscission site: IST1 and CHMP2B are minimally disrupted, while CHMP1B (along with CHMP4B and CHMP3) shows progressively severe mislocalization, establishing CHMP2A as an upstream organizer required for correct CHMP1B positioning during abscission.\",\n      \"method\": \"CHMP2A knockout; live-cell imaging; structured illumination microscopy (SIM); correlative light-electron microscopy; dual-protein imaging of ESCRT-III subunits\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with multiple imaging modalities and epistatic ordering of subunits, single lab\",\n      \"pmids\": [\"40928930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Conserved leucine residues L192 and L195 within the MIM (MIT-interacting motif) domain of CHMP1B are required for interaction with USP8/UBPY, whereas the ubiquitination status of CHMP1B does not affect this interaction; deletion of the MIM domain abolishes binding.\",\n      \"method\": \"HTRF interaction assay; CHMP1B point-mutant and deletion analysis (L192A/L195A and MIM deletion); comparison of ubiquitin-deficient CHMP1B mutant (4K→R) vs wild-type binding to USP8\",\n      \"journal\": \"SLAS discovery : advancing life sciences R & D\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative interaction assay with multiple CHMP1B mutants, single lab\",\n      \"pmids\": [\"35995394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Calpain-7 N-terminal tandem MIT domain directly interacts with CHMP1B; the interaction was confirmed by pulldown assay using recombinant proteins. Overexpression of GFP-CHMPs or dominant-negative VPS4B caused calpain-7 accumulation in perinuclear puncta overlapping with endocytosed EGF, and endogenous calpain-7 partitions largely to cytosol with a small fraction in particulate fractions.\",\n      \"method\": \"Strep-tag pulldown from stable HEK293T transfectants; recombinant protein pulldown; fluorescence microscopy; subcellular fractionation\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct recombinant protein pulldown plus subcellular fractionation, single lab\",\n      \"pmids\": [\"18316332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CHMP1B (along with CHMP1A, CHMP5, and IST1 as accessory ESCRT-III proteins) is required for intraluminal vesicle formation in Drosophila recycling endosomes but, unlike core ESCRTs, is not involved in degradation of ubiquitinated proteins in late endosomes, revealing a specific ubiquitin-independent role in Rab11a-exosome generation.\",\n      \"method\": \"Drosophila genetic knockdown; comparative proteomics of Rab11a-enriched vs. total exosome preparations; CHMP5 siRNA knockdown in HCT116 cells; ILV formation assay\",\n      \"journal\": \"Journal of extracellular vesicles\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo Drosophila genetics plus human cell knockdown with defined vesicle biogenesis readout, single lab\",\n      \"pmids\": [\"36872252\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CHMP1B is an ESCRT-III subunit that, together with IST1, forms a double-stranded helical copolymer that coats positively curved membranes to drive normal-topology membrane scission events including cytokinetic abscission, early endosomal tubule scission, and fatty acid transfer at lipid droplet–peroxisome contacts; its C-terminal MIM1 motif mediates high-affinity binding to MIT-domain proteins (spastin, VPS4, LIP5, UBPY/USP8, AMSH, MITD1, calpain-7), recruiting them to their sites of action, while dynamic ubiquitination of CHMP1B—written by LZTR1-CUL3 and erased by USP8—regulates its membrane recruitment and ESCRT-III polymer assembly in response to EGF signaling and endosomal repair.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CHMP1B is an ESCRT-III subunit that, with IST1, builds a one-start double-stranded helical copolymer in which 'open' interlocked CHMP1B subunits form the inner strand and 'closed' IST1 subunits form the outer strand, an arrangement that uniquely coats positively curved membranes and thereby drives normal-topology membrane remodeling events [#0]. Activation of CHMP1B for assembly involves release of an autoinhibitory α5 helix from the ESCRT-III core, and the resulting IST1–CHMP1B interaction is required for cytokinetic abscission [#3]. At constricted membranes the copolymer imposes leaflet-level lipid asymmetry, with two CHMP1B phenylalanines creating a helical hydrophobic defect on the outer leaflet that recruits polyunsaturated lipid tails [#20]. CHMP1B performs scission across multiple normal-topology sites: it scissions early endosomal tubular carriers to recycle transferrin and mannose-6-phosphate receptors, with SNX15 and CHMP1B alternately recruiting IST1 to distinct endosomal subdomains [#18, #17], and is recruited by spastin to lipid droplets to support fatty acid transfer to peroxisomes [#13]. Its C-terminal MIM1 motif is a high-affinity docking site for MIT-domain proteins, including spastin—for which CHMP1B is the midbody-targeting signal [#1, #2]—VPS4A, whose ATPase it stimulates [#4, #8], LIP5 [#9, #11], the deubiquitinases AMSH and UBPY/USP8 [#5, #6, #23], and MITD1 [#10], while calpain-7 binds a noncanonical second α-helical region [#16, #24]. CHMP1B is itself dynamically ubiquitinated within a polymerization-sensitive loop—written by the LZTR1-CUL3 ligase and erased by USP8—and this modification governs its membrane recruitment and ESCRT-III assembly during EGF and VEGFR2 receptor trafficking; LZTR1 mutations that reduce CHMP1B ubiquitination cause endosomal accumulation and sustained VEGFR2 signaling in the context of Noonan syndrome [#12, #15, #23]. ESCRT-III subunit order also constrains CHMP1B function, as CHMP2A acts upstream to position CHMP1B correctly at the abscission site [#22].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established the first functional partner of CHMP1B by showing it binds and modulates the microtubule-severing ATPase spastin, linking an ESCRT-III protein to membrane trafficking and microtubule regulation.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, in vitro pull-down, fragment complementation and dominant-negative spastin rescue in Cos-7/PC12 cells\",\n      \"pmids\": [\"15537668\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the interaction not yet resolved\", \"Did not define the spastin recruitment site or in vivo cytokinesis role\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined the molecular logic of MIT-domain recognition by showing the VPS4A MIT domain binds the CHMP1B C-terminus with a conserved leucine, framing ESCRT-III tails as TPR-completing ligands.\",\n      \"evidence\": \"NMR solution structure of VPS4A MIT domain, SPR affinity measurement and mutagenesis\",\n      \"pmids\": [\"16174732\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Modest ~20 µM affinity leaves cellular avidity contributors undefined\", \"Did not address how binding triggers VPS4 disassembly activity\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed that VPS4 and the deubiquitinase AMSH compete for the CHMP1B C-terminus, suggesting coordinated control of ESCRT-III disassembly and cargo deubiquitination.\",\n      \"evidence\": \"Co-IP and competitive binding assay\",\n      \"pmids\": [\"16760479\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, no structure of the competitive interface\", \"Functional consequence of competition not directly tested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified UBPY/USP8 as a CHMP1B-binding deubiquitinase whose MIT domain is required for endosomal localization and EGFR degradation, placing CHMP1B in receptor downregulation.\",\n      \"evidence\": \"Co-IP, UBPY MIT-deletion localization and EGFR degradation rescue\",\n      \"pmids\": [\"17711858\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not map the CHMP1B residues required for binding\", \"Direct role of CHMP1B (vs CHMP1A) in EGFR degradation not isolated\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Resolved the structural basis for CHMP1B as the midbody-targeting signal for spastin and mapped overlapping LIP5/VPS4 binding regions on the CHMP1B C-terminus.\",\n      \"evidence\": \"2.5 Å crystal structure of CHMP1B tail/spastin MIT, spastin point mutants and cytokinesis assays; separate in vitro LIP5 binding/truncation analysis\",\n      \"pmids\": [\"18997780\", \"18385515\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether a true second VPS4 site exists on CHMP1B remained inferential\", \"Conformational dependence of LIP5 binding only partially defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated that CHMP1B autoinhibition by the α5 helix gates polymerization and that IST1–CHMP1B assembly is required for abscission, establishing the activation switch for this copolymer.\",\n      \"evidence\": \"In vitro helical assembly, core-α5 interface mutagenesis, abscission assay and crystal structures of IST1/CHMP3 cores\",\n      \"pmids\": [\"19525971\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger that releases autoinhibition in vivo not identified\", \"Copolymer architecture not yet resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Provided a mechanistic model for how CHMP1B activates VPS4A, showing its C-terminal fragment threads into the VPS4A pore to stimulate ATPase activity.\",\n      \"evidence\": \"In vitro ATPase assays with purified proteins, VPS4A pore-loop mutagenesis and liposome oligomerization\",\n      \"pmids\": [\"20805225\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab reconstitution without structure of the threaded state\", \"Relevance to full-length polymerized CHMP1B not tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified calpain-7 as a noncanonical CHMP1B partner binding a second α-helical region, and showed CHMP1B/IST1 form a ternary complex regulating calpain-7 autolysis and membrane partitioning.\",\n      \"evidence\": \"Recombinant pull-down with truncation mutants, Co-IP, autolysis assay and subcellular fractionation\",\n      \"pmids\": [\"21616915\", \"18316332\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological substrate of calpain-7 at ESCRT sites unknown\", \"Single lab, no structure of the noncanonical interface\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Refined LIP5 and MITD1 recognition of CHMP1B, showing LIP5 uses canonical MIM1 contacts but requires simultaneous CHMP5 binding to assemble stable VPS4 complexes, while MITD1 is recruited to the midbody by CHMP1B to regulate IST1-VPS4.\",\n      \"evidence\": \"NMR structures, SPR, cellular Co-IP (LIP5); Co-IP and siRNA abscission assays (MITD1)\",\n      \"pmids\": [\"23105106\", \"23015756\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How these competing adaptors are temporally ordered at one site unclear\", \"MITD1 study was single-lab Medium confidence\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Delivered the atomic architecture of the CHMP1B/IST1 copolymer and an atomic-resolution LIP5–CHMP1B/CHMP5 structure, revealing a unique positive-curvature external coat and the conformational coupling of ESCRT-III binding to LIP5/VPS4 stimulation.\",\n      \"evidence\": \"4 Å cryo-EM of the copolymer plus membrane assays; 1 Å crystal structure of LIP5NTD with CHMP5/CHMP1B MIMs and ATPase assay\",\n      \"pmids\": [\"26634441\", \"25637630\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo membrane substrates of the external coat not yet enumerated\", \"How curvature sensing selects sites in cells unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established dynamic ubiquitination of CHMP1B—erased by USP8 within a polymerization-sensitive loop—as a regulatory switch for membrane recruitment and EGFR trafficking conserved into Drosophila.\",\n      \"evidence\": \"Ubiquitination assays, USP8 Co-IP, size-exclusion of a 500 kDa IST1 complex, EGF pulse-chase and Drosophila loss-of-function\",\n      \"pmids\": [\"29933386\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The ligase writing the modification was not yet identified\", \"Quantitative stoichiometry of ubiquitin on polymer vs soluble CHMP1B unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended CHMP1B function to interorganelle lipid transfer and to endosomal motility control, showing spastin recruits CHMP1B/IST1 to lipid droplets for fatty acid trafficking and that loss of CHMP1B produces protrudin/KIF5-dependent protrusions.\",\n      \"evidence\": \"Live imaging, loss-of-function, fatty acid trafficking and peroxidation assays; siRNA epistasis with spastin/protrudin/KIF5 and BMP receptor distribution\",\n      \"pmids\": [\"31227594\", \"31587092\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether scission per se mediates FA transfer not directly proven\", \"Both single-lab studies without structural correlates\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified the LZTR1-CUL3 ligase as the writer of CHMP1B ubiquitination controlling recycling-endosome dynamics, and linked Noonan-syndrome LZTR1 mutations to reduced CHMP1B ubiquitination, endosomal accumulation and sustained VEGFR2 signaling.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, LZTR1 knockout mouse and endothelial knockdown with trafficking imaging and VEGFR2 readout\",\n      \"pmids\": [\"32175818\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ubiquitination sites and chain type on CHMP1B by LZTR1 not mapped\", \"Single lab; vascular phenotype mechanism partly correlative\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Refined CHMP1B–USP8 recognition to specific MIM leucines independent of ubiquitin status, and showed pathogen and host ubiquitin signals on VPS4A tune CHMP1B engagement.\",\n      \"evidence\": \"HTRF with CHMP1B L192A/L195A and MIM-deletion mutants (USP8); HCV-induced VPS4A K23/K121 ubiquitylation, Co-IP, ATPase and infectivity assays\",\n      \"pmids\": [\"35995394\", \"35044214\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether USP8 recognition mode differs across MIT proteins not resolved\", \"Generality of VPS4A ubiquitin-gated CHMP1B binding beyond HCV unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined the membrane-physical mechanism and the cargo-specific, ubiquitin-independent scission roles of the CHMP1B/IST1 copolymer at endosomes and exosomes, with a chemical tool isolating the recycling function from cytokinesis and MVB sorting.\",\n      \"evidence\": \"Cryo-EM of brominated lipids plus MD; live-imaging siRNA of SNX15/CHMP1B endosomal subdomains; small-molecule IST1-CHMP1B disruptor with transferrin recycling and LC3 readouts; Drosophila/HCT116 Rab11a-exosome ILV assays\",\n      \"pmids\": [\"36624348\", \"37926552\", \"38635626\", \"36872252\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How distinct subdomain recruitment cues (SNX15 vs CHMP1B) are coordinated unclear\", \"Trigger for noncanonical LC3 lipidation on stalled endosomes undefined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Reported a nuclear/chromatin-associated property of CHMP1B mediated by its N-terminal region, raising a possible role outside membrane scission.\",\n      \"evidence\": \"Fluorescence microscopy of nuclear foci, N-terminal mutagenesis and interspecies VPS4 recruitment\",\n      \"pmids\": [\"36221007\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No biochemical or structural validation of chromatin binding\", \"Functional consequence of nuclear localization untested\", \"Single lab, not independently confirmed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established that CHMP1B positioning at the abscission site is hierarchically controlled, with CHMP2A acting upstream to organize correct CHMP1B localization.\",\n      \"evidence\": \"CHMP2A knockout with live imaging, SIM and correlative light-electron microscopy of ESCRT-III subunits\",\n      \"pmids\": [\"40928930\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular interface by which CHMP2A directs CHMP1B not defined\", \"Whether the same hierarchy operates at endosomes unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the various competing MIT-domain effectors and the ubiquitination cycle are temporally choreographed to select among CHMP1B's distinct scission sites (abscission, endosomal tubules, lipid-droplet contacts, exosome biogenesis) remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified in vivo model coupling ubiquitination state to site selection\", \"Site-specific determinants distinguishing normal-topology scission contexts undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 3, 20]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [20]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 8, 11]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 2, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 12]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [6, 18, 25]},\n      {\"term_id\": \"GO:0005811\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [12, 24]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 3, 10, 22]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [13, 14, 18, 25]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [12, 15]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [6, 17, 18]}\n    ],\n    \"complexes\": [\"CHMP1B-IST1 ESCRT-III copolymer\", \"ESCRT-III\", \"calpain-7/CHMP1B/IST1 ternary complex\"],\n    \"partners\": [\"IST1\", \"SPAST\", \"VPS4A\", \"LIP5\", \"USP8\", \"AMSH\", \"MITD1\", \"CAPN7\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}