{"gene":"CAPZB","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":1995,"finding":"Human CAPZB (β subunit of Cap Z) binds F-actin via its C-terminal domain; cosedimentation assays showed binding affinity equal to chicken Cap Z. Amino acid substitutions of two conserved leucines in the C-terminal actin-binding domain of the chicken β subunit resulted in significant decreases in F-actin binding activity, identifying these residues as critical for actin binding. The human CAPZB gene was mapped to chromosome 1p36.1.","method":"F-actin cosedimentation assay; site-directed mutagenesis of conserved leucine residues; chromosomal mapping","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution (cosedimentation) combined with mutagenesis in a single rigorous study","pmids":["7665558"],"is_preprint":false},{"year":2017,"finding":"CAPZB regulates actin filament length at the mitotic cortex. Loss-of-function of CAPZB (along with CFL1 and DIAPH1) altered mitotic cortex thickness, and both increasing and decreasing thickness decreased cortical tension, indicating the mitotic cortex is poised near a tension maximum. CAPZB knockdown thus modulates cell surface tension through control of cortical actin network architecture.","method":"RNAi knockdown with live-cell imaging of cortex thickness; cortical tension measurements (micropipette aspiration); computational modeling","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KD with defined cellular phenotype, quantitative tension measurements, computational model; replicated across multiple conditions","pmids":["28530659"],"is_preprint":false},{"year":2019,"finding":"CAPZB (CAPZ) restrains actomyosin contractility by capping actin barbed ends: Capzb conditional knockout in mouse hepatocytes led to altered stress fiber and focal adhesion dynamics, enhanced myosin activity, increased traction forces, and increased liver stiffness. This mechanical change activated YAP in parallel to the Hippo pathway, causing hepatocyte proliferation and liver overgrowth. ROCK inhibition or Yap1 deletion reversed these phenotypes, placing CAPZB upstream of mechanotransduction-driven YAP activation.","method":"Conditional knockout mouse (Capzb flox); traction force microscopy; atomic force microscopy (liver stiffness); YAP localization/activity assays; genetic epistasis with ROCK inhibitor (fasudil) and Yap1 deletion","journal":"Journal of hepatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO in vivo and in vitro with multiple orthogonal methods (traction forces, stiffness, genetic epistasis) establishing pathway position","pmids":["30878582"],"is_preprint":false},{"year":2017,"finding":"CAPZB is required for stereocilia length and width regulation in cochlear hair cells. CAPZB is present at ~100 copies per stereocilium and concentrates at stereocilia tips as development progresses. Hair-cell-specific Capzb deletion (Atoh1-Cre) eliminated auditory and vestibular function; Capzb-null stereocilia initially developed normally but then shortened and disappeared, with concomitant decrease in width. Overexpression of CAPZB2 prevented normal elongation and caused irregular widening, indicating capping protein participates in stereocilia widening by preventing newly elongating actin filaments from depolymerizing.","method":"Hair-cell-specific conditional knockout (Atoh1-Cre); in utero electroporation overexpression; phalloidin labeling with quantitative imaging of stereocilia dimensions; auditory brainstem response and vestibular assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO and overexpression with quantitative morphological and functional readouts in a single rigorous study","pmids":["28899994"],"is_preprint":false},{"year":2016,"finding":"CAPZB controls spindle orientation independently of its classical role in actin cytoskeleton. RNAi depletion of CAPZB in a micropatterning/Gαi-induction cell model disrupted spindle orientation. Mechanistically, CAPZB regulates the assembly, stability, and motor activity of the dynein/dynactin complex at the cell cortex and controls mitotic microtubule dynamics. In vivo, CAPZB controls planar divisions in the developing neuroepithelium.","method":"RNAi screen in micropatterned cells with localized Gαi recruitment; live imaging of spindle orientation; dynein/dynactin complex analysis; in vivo neuroepithelium assay","journal":"Current biology : CB","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined cellular phenotype by RNAi with in vivo validation, but mechanistic detail on dynein/dynactin derived from single lab study","pmids":["28803871"],"is_preprint":false},{"year":2016,"finding":"CAPZB regulates cell morphology, differentiation, and neural crest migration in craniofacial morphogenesis. In zebrafish capzb−/− mutants, loss of capzb disrupted neural crest cell migration, caused cleft phenotype by loss of the median cell population, and disrupted trunk neural crest migration (melanophore disorganization). capzb was required for differentiation of both myogenic stem cells and neural crest cells. capzb overexpression caused embryonic lethality, indicating dosage sensitivity.","method":"Zebrafish capzb null mutant and overexpression; live imaging of neural crest migration; whole-mount in situ hybridization; human case with de novo balanced chromosomal translocation disrupting CAPZB","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function in zebrafish with defined cellular phenotypes; supported by human genetic evidence","pmids":["26758871"],"is_preprint":false},{"year":2016,"finding":"In fission yeast, TORC2-dependent phosphorylation of the actin-capping protein Acp1 (equivalent of mammalian CAPZα) controls cytokinetic actomyosin ring (CAR) stability and modulates Acp1-Acp2 (CAPZA-CAPZB) heterodimer formation; disruption of TORC2 or this phosphorylation impairs CAR morphology and constriction.","method":"Fission yeast genetics; co-immunoprecipitation; phosphorylation analysis; live-cell imaging of CAR dynamics","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and biochemical evidence in yeast ortholog system; directly demonstrates CAPZA-CAPZB heterodimer formation regulated by phosphorylation","pmids":["27206859"],"is_preprint":false},{"year":2016,"finding":"CAPZB knockdown in epithelioid sarcoma cells inhibited cell growth, invasion, and migration. Proteomic profiling after CAPZB silencing identified INI1 (SWI/SNF complex) as a potential upstream regulator of CAPZB; silencing CAPZB decreased INI1 protein expression in INI1-positive cells, while INI1 induction in INI1-deficient cells increased CAPZB mRNA.","method":"siRNA knockdown in EpiS cell lines; invasion/migration assays; iTRAQ quantitative proteomics; INI1 overexpression; IPA pathway analysis","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined phenotypic readouts and proteomic pathway analysis; single lab study","pmids":["26965049"],"is_preprint":false},{"year":2009,"finding":"A spermatid-specific CAPZ heterodimer (CAPZA3/CAPZB variant isoform) is essential for F-actin network organization during spermiation. In repro32 mice with a missense mutation in Capza3, CAPZB variant isoform localization was altered concurrent with disruption of the F-actin network, failure to shed excess cytoplasm, and disorganization of the sperm flagellum midpiece. This established that the CAPZA3/CAPZB heterodimer regulates F-actin dynamics required for cytoplasm removal and midpiece integrity.","method":"ENU-induced mutant mouse (repro32); candidate-gene sequencing; immunofluorescence localization of CAPZB variant; F-actin staining; sperm morphology and motility analysis","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with localization and structural readouts; single lab, orthologous mouse model","pmids":["19341723"],"is_preprint":false},{"year":2020,"finding":"CAPZB localizes to stereocilia tips at row 2 of cochlear inner hair cells in a mechanotransduction-dependent manner. In transduction mutants (Tmc1/Tmc2 or Tmie knockouts), CAPZB and its partner TWF2 failed to concentrate at row 2 tips. Block of transduction channels also redistributed CAPZB from row 2 tips, demonstrating that mechanotransduction activity specifies CAPZB subcellular localization at stereocilia.","method":"Mouse cochlear hair cell immunofluorescence; Tmc1/Tmc2 and Tmie knockout models; transduction channel blocker treatment; quantitative confocal imaging","journal":"Current biology : CB","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with genetic and pharmacological perturbation linked to functional (transduction) state; single lab","pmids":["31902726"],"is_preprint":false},{"year":2013,"finding":"Vasopressin treatment of kidney collecting duct cells caused significant changes in abundance of CAPZB at the apical plasma membrane. CAPZB was identified as one of five F-actin end-binding proteins involved in vasopressin-induced F-actin reorganization, which is required for aquaporin-2 apical trafficking and increased water permeability.","method":"Stable isotope quantitative proteomics (SILAC); surface biotinylation; live-cell F-actin imaging; vasopressin stimulation of mouse cortical collecting duct cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Low","confidence_rationale":"Tier 3 / Weak — CAPZB identified as a regulated component by proteomics; no direct functional perturbation of CAPZB itself was performed","pmids":["24085853"],"is_preprint":false},{"year":2013,"finding":"Quaking (QK) promotes inclusion of Capzb exon 9 in opposition to repression by polypyrimidine tract-binding protein (PTB) during muscle cell differentiation. Mass spectrometry of proteins selected by the Capzb exon 9 intron (containing ACUAA STAR motifs) via RNA affinity chromatography identified QK as a splicing regulator of this exon, establishing a mechanism for muscle-specific alternative splicing of CAPZB.","method":"RNA affinity chromatography with mass spectrometry; QK depletion by RNAi; RT-PCR splicing assays; myoblast-to-myotube differentiation model","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA affinity chromatography plus functional RNAi knockdown with splicing readout; single lab with multiple orthogonal methods","pmids":["23525800"],"is_preprint":false},{"year":2025,"finding":"ALIX recruits actin-capping proteins CAPZA1/CAPZB to prevent branched filamentous actin (F-actin) accumulation around multivesicular bodies (MVBs), enabling MVB trafficking to the cell periphery for exosome secretion. PTPN23 (competitor of ALIX for syntenin binding) does not recruit CAPZA1/CAPZB. This ALIX–CAPZA1/CAPZB mechanism is required for the pro-tumorigenic exosome secretion pathway.","method":"Co-immunoprecipitation; genetic perturbation (PTPN23 knockout, ALIX depletion); F-actin visualization around MVBs; exosome secretion assays in mouse and human cancer cells","journal":"Developmental cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and functional genetic perturbation with defined cellular readout; single lab","pmids":["40185104"],"is_preprint":false},{"year":2026,"finding":"HDAC8 desuccinylates CAPZB at lysine residues K57, K95, and K235. CAPZB regulates cytoskeletal remodeling and fibroblast-to-myofibroblast differentiation by capping the barbed end of F-actin. Desuccinylation (removal of succinyl groups) inhibits CAPZB function and promotes cytoskeletal remodeling; mutation of the modification sites confirmed that succinylation inhibits CAPZB activity. HDAC8 physically interacts with CAPZB and its pro-fibrotic role as a desuccinylase was verified in vitro and in vivo.","method":"Mass spectrometry identification of succinylation sites; site-directed mutagenesis of K57/K95/K235; gain- and loss-of-function in fibroblasts and in vivo mouse model; Co-IP of HDAC8 with CAPZB; F-actin capping and cytoskeletal assays","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — identification of PTM sites by MS, mutagenesis confirming functional relevance, identification of writer enzyme (HDAC8) by Co-IP, in vitro and in vivo validation in single study","pmids":["42050207"],"is_preprint":false}],"current_model":"CAPZB encodes the β subunit of the heterodimeric F-actin barbed-end capping protein (Cap Z), which physically blocks actin polymerization at barbed ends via C-terminal residues; it restrains actomyosin contractility and cortical tension by limiting actin filament length, localizes to actin-rich structures (stereocilia tips, cortex, MVBs) where it controls dimensions and dynamics, participates in spindle orientation by regulating dynein/dynactin at the cell cortex, is recruited to MVBs by ALIX to enable exosome secretion, and is regulated post-translationally by HDAC8-mediated desuccinylation at K57/K95/K235, with muscle-specific isoforms generated by QK/PTB-controlled alternative splicing of exon 9."},"narrative":{"mechanistic_narrative":"CAPZB encodes the β subunit of the heterodimeric F-actin barbed-end capping protein (CapZ), which binds F-actin through C-terminal residues—two conserved leucines being critical for binding activity—and pairs with a CAPZA α subunit to cap filament barbed ends and thereby set actin filament length [PMID:7665558, PMID:27206859]. By limiting barbed-end elongation, CAPZB controls the architecture and mechanics of actin networks: it tunes mitotic cortex thickness and cortical tension [PMID:28530659], and restrains actomyosin contractility such that its loss in hepatocytes raises traction forces and tissue stiffness, activating YAP-driven proliferation through ROCK-dependent mechanotransduction [PMID:30878582]. This length-control function underlies its roles in specialized actin-based structures, including cochlear hair-cell stereocilia, where CAPZB concentrates at tips in a mechanotransduction-dependent manner together with TWF2 and is required to maintain stereocilia length and width [PMID:28899994, PMID:31902726]. CAPZB also acts beyond bulk actin regulation: it controls mitotic spindle orientation by regulating dynein/dynactin assembly and motor activity at the cell cortex and governs planar divisions in the developing neuroepithelium [PMID:28803871], and it is recruited by ALIX to multivesicular bodies to prevent branched F-actin accumulation, enabling MVB trafficking and exosome secretion [PMID:40185104]. CAPZB is required for neural crest migration and craniofacial morphogenesis, with a human balanced translocation disrupting the gene [PMID:26758871], and its activity is regulated post-translationally by HDAC8-mediated desuccinylation at K57/K95/K235, with muscle-specific isoforms generated by QK/PTB-controlled alternative splicing of exon 9 [PMID:42050207, PMID:23525800].","teleology":[{"year":1995,"claim":"Established that human CAPZB is a functional F-actin capping subunit and pinpointed the C-terminal residues responsible for actin binding, defining the molecular basis of its activity.","evidence":"F-actin cosedimentation and site-directed mutagenesis of conserved leucines; chromosomal mapping to 1p36.1","pmids":["7665558"],"confidence":"High","gaps":["Did not address regulation of capping in cells","Heterodimer assembly with CAPZA not examined in this study"]},{"year":2009,"claim":"Showed that a tissue-specific CAPZ heterodimer organizes F-actin in a developmental context, extending CAPZB function to spermiation.","evidence":"ENU mutant mouse (repro32) with Capza3 missense mutation; CAPZB variant localization, F-actin staining, sperm morphology","pmids":["19341723"],"confidence":"Medium","gaps":["Effect is via the CAPZA3 partner, not CAPZB itself","Single orthologous mouse model"]},{"year":2013,"claim":"Identified how muscle-specific CAPZB isoforms are generated, defining QK and PTB as antagonistic splicing regulators of exon 9.","evidence":"RNA affinity chromatography/MS, QK RNAi, RT-PCR splicing assays in myoblast differentiation","pmids":["23525800"],"confidence":"Medium","gaps":["Functional consequence of the two isoforms on capping activity not resolved","Single lab"]},{"year":2013,"claim":"Implicated CAPZB in regulated apical F-actin reorganization downstream of vasopressin, linking it to membrane trafficking.","evidence":"SILAC proteomics, surface biotinylation, vasopressin stimulation of collecting duct cells","pmids":["24085853"],"confidence":"Low","gaps":["No direct functional perturbation of CAPZB performed","Correlative proteomic association only"]},{"year":2016,"claim":"Revealed a moonlighting role for CAPZB in spindle orientation through regulation of cortical dynein/dynactin, distinct from its bulk actin function.","evidence":"RNAi in micropatterned Gαi-induction cells, spindle orientation imaging, dynein/dynactin analysis, in vivo neuroepithelium","pmids":["28803871"],"confidence":"Medium","gaps":["Mechanism of dynein/dynactin regulation derived from single lab","Direct biochemical link to dynein/dynactin not established"]},{"year":2016,"claim":"Demonstrated organismal requirements for CAPZB in neural crest migration, differentiation, and craniofacial development, with human genetic support.","evidence":"Zebrafish capzb null and overexpression, neural crest imaging, in situ hybridization, human translocation case","pmids":["26758871"],"confidence":"Medium","gaps":["Dosage sensitivity mechanism unresolved","Human evidence limited to a single translocation case"]},{"year":2016,"claim":"Linked CAPZB to tumor cell invasion and placed it within an INI1/SWI-SNF regulatory relationship in epithelioid sarcoma.","evidence":"siRNA knockdown, invasion/migration assays, iTRAQ proteomics, INI1 induction in EpiS cells","pmids":["26965049"],"confidence":"Medium","gaps":["INI1-CAPZB regulation is correlative","Single lab and cell-line context"]},{"year":2016,"claim":"Showed that CAPZA-CAPZB heterodimer formation and capping function are controlled by TORC2-dependent phosphorylation, establishing regulated heterodimer assembly.","evidence":"Fission yeast genetics, Co-IP, phosphorylation analysis, live imaging of cytokinetic actomyosin ring","pmids":["27206859"],"confidence":"Medium","gaps":["Demonstrated in yeast orthologs (Acp1/Acp2)","Conservation of TORC2 control in mammalian CAPZB not tested here"]},{"year":2017,"claim":"Quantified how CAPZB tunes mitotic cortex architecture and cortical tension, showing the cortex is poised near a tension maximum.","evidence":"RNAi knockdown, live imaging of cortex thickness, micropipette aspiration tension measurement, computational modeling","pmids":["28530659"],"confidence":"High","gaps":["Does not separate CAPZB-specific from general capping effects","Downstream signaling consequences not examined"]},{"year":2017,"claim":"Defined CAPZB as essential for stereocilia dimension control and hearing/balance, showing capping prevents depolymerization of newly elongated filaments.","evidence":"Atoh1-Cre conditional KO, in utero electroporation overexpression, quantitative phalloidin imaging, ABR and vestibular assays","pmids":["28899994"],"confidence":"High","gaps":["Molecular partners at stereocilia tips not yet defined in this study","Width-control mechanism inferred from morphology"]},{"year":2019,"claim":"Established CAPZB upstream of mechanotransduction-driven YAP activation, linking actin capping to tissue stiffness and organ growth.","evidence":"Capzb conditional KO mouse, traction force and atomic force microscopy, YAP assays, epistasis with ROCK inhibitor and Yap1 deletion","pmids":["30878582"],"confidence":"High","gaps":["Direct molecular coupling between capping loss and YAP not fully mapped","Tissue-specificity beyond hepatocytes not tested"]},{"year":2020,"claim":"Showed that mechanotransduction activity itself specifies CAPZB subcellular localization at stereocilia row 2 tips, alongside TWF2.","evidence":"Cochlear hair cell immunofluorescence, Tmc1/Tmc2 and Tmie KO models, channel blocker, confocal imaging","pmids":["31902726"],"confidence":"Medium","gaps":["Signal coupling transduction to CAPZB targeting unknown","Single lab"]},{"year":2025,"claim":"Identified ALIX as the recruiter of CAPZA1/CAPZB to MVBs, defining a capping-dependent mechanism enabling exosome secretion.","evidence":"Co-IP, PTPN23 KO and ALIX depletion, F-actin imaging around MVBs, exosome secretion assays in cancer cells","pmids":["40185104"],"confidence":"Medium","gaps":["Structural basis of ALIX-CAPZ interaction not resolved","Single lab"]},{"year":2026,"claim":"Defined succinylation as a post-translational switch on CAPZB and HDAC8 as the desuccinylase, linking CAPZB regulation to fibroblast differentiation.","evidence":"MS site identification, K57/K95/K235 mutagenesis, gain/loss-of-function in fibroblasts and mouse model, HDAC8-CAPZB Co-IP, capping assays","pmids":["42050207"],"confidence":"High","gaps":["Succinyl writer enzyme not identified","Generality across cell types beyond fibroblasts not established"]},{"year":null,"claim":"How CAPZB switches between bulk cortical capping, structure-specific localization (stereocilia tips, MVBs), and its non-canonical dynein/dynactin role remains unresolved at the mechanistic level.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of mammalian CAPZA-CAPZB heterodimer in the corpus","Recruitment logic to distinct subcellular sites not unified","Direct biochemical mechanism of dynein/dynactin regulation undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,1,3,13]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,2,3,13]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,2,10]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[12]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1,4]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[12]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,5]}],"complexes":["CapZ (F-actin capping protein heterodimer)"],"partners":["CAPZA1","CAPZA3","ALIX","TWF2","HDAC8"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P47756","full_name":"F-actin-capping protein subunit beta","aliases":["CapZ beta"],"length_aa":272,"mass_kda":30.6,"function":"F-actin-capping proteins bind in a Ca(2+)-independent manner to the fast growing ends of actin filaments (barbed end) thereby blocking the exchange of subunits at these ends. Unlike other capping proteins (such as gelsolin and severin), these proteins do not sever actin filaments. Plays a role in the regulation of cell morphology and cytoskeletal organization. Forms, with CAPZB, the barbed end of the fast growing ends of actin filaments in the dynactin complex and stabilizes dynactin structure. The dynactin multiprotein complex activates the molecular motor dynein for ultra-processive transport along microtubules (By similarity)","subcellular_location":"Cytoplasm, cytoskeleton; Cytoplasm, myofibril, sarcomere","url":"https://www.uniprot.org/uniprotkb/P47756/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/CAPZB","classification":"Common Essential","n_dependent_lines":1165,"n_total_lines":1208,"dependency_fraction":0.9644039735099338},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000077549","cell_line_id":"CID000621","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"membrane","grade":3},{"compartment":"vesicles","grade":3},{"compartment":"nucleoplasm","grade":1}],"interactors":[{"gene":"ACTG1","stoichiometry":10.0},{"gene":"CALD1","stoichiometry":10.0},{"gene":"DCTN3","stoichiometry":10.0},{"gene":"CAPZA2","stoichiometry":10.0},{"gene":"MTPN","stoichiometry":10.0},{"gene":"CAPZA1","stoichiometry":10.0},{"gene":"ACTR1A","stoichiometry":10.0},{"gene":"DCTN1;DKFZP686E0752","stoichiometry":10.0},{"gene":"FAM21A","stoichiometry":10.0},{"gene":"VPS35","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000621","total_profiled":1310},"omim":[{"mim_id":"612412","title":"SPERMATOGENESIS AND CENTRIOLE-ASSOCIATED PROTEIN 1-LIKE; SPATC1L","url":"https://www.omim.org/entry/612412"},{"mim_id":"612306","title":"THYROID-STIMULATING HORMONE LEVEL QUANTITATIVE TRAIT LOCUS 1; TSHQTL1","url":"https://www.omim.org/entry/612306"},{"mim_id":"605143","title":"ACTIN-RELATED PROTEIN 1A; ACTR1A","url":"https://www.omim.org/entry/605143"},{"mim_id":"601580","title":"CAPPING PROTEIN, ALPHA-1; CAPZA1","url":"https://www.omim.org/entry/601580"},{"mim_id":"601572","title":"CAPPING PROTEIN, BETA; CAPZB","url":"https://www.omim.org/entry/601572"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CAPZB"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P47756","domains":[{"cath_id":"3.90.1150.210","chopping":"91-272","consensus_level":"medium","plddt":89.8471,"start":91,"end":272}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P47756","model_url":"https://alphafold.ebi.ac.uk/files/AF-P47756-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P47756-F1-predicted_aligned_error_v6.png","plddt_mean":91.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CAPZB","jax_strain_url":"https://www.jax.org/strain/search?query=CAPZB"},"sequence":{"accession":"P47756","fasta_url":"https://rest.uniprot.org/uniprotkb/P47756.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P47756/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P47756"}},"corpus_meta":[{"pmid":"28530659","id":"PMC_28530659","title":"Actin cortex architecture regulates cell surface tension.","date":"2017","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/28530659","citation_count":313,"is_preprint":false},{"pmid":"23525800","id":"PMC_23525800","title":"Quaking and PTB control overlapping splicing regulatory networks during muscle cell differentiation.","date":"2013","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/23525800","citation_count":133,"is_preprint":false},{"pmid":"37879141","id":"PMC_37879141","title":"Pan-cancer genetic analysis of disulfidptosis-related gene set.","date":"2023","source":"Cancer genetics","url":"https://pubmed.ncbi.nlm.nih.gov/37879141","citation_count":127,"is_preprint":false},{"pmid":"30878582","id":"PMC_30878582","title":"F-actin dynamics regulates mammalian organ growth and cell fate maintenance.","date":"2019","source":"Journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/30878582","citation_count":71,"is_preprint":false},{"pmid":"28183280","id":"PMC_28183280","title":"Whole genome scan reveals the genetic signature of African Ankole cattle breed and potential for higher quality beef.","date":"2017","source":"BMC genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28183280","citation_count":67,"is_preprint":false},{"pmid":"24085853","id":"PMC_24085853","title":"Quantitative apical membrane proteomics reveals vasopressin-induced actin dynamics in collecting duct cells.","date":"2013","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/24085853","citation_count":60,"is_preprint":false},{"pmid":"31902726","id":"PMC_31902726","title":"Mechanotransduction-Dependent Control of Stereocilia Dimensions and Row Identity in Inner Hair Cells.","date":"2020","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/31902726","citation_count":60,"is_preprint":false},{"pmid":"19341723","id":"PMC_19341723","title":"A missense mutation in the Capza3 gene and disruption of F-actin organization in spermatids of repro32 infertile male mice.","date":"2009","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/19341723","citation_count":56,"is_preprint":false},{"pmid":"7665558","id":"PMC_7665558","title":"Sequence analysis and chromosomal localization of human Cap Z. 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F-actin via its C-terminal domain; cosedimentation assays showed binding affinity equal to chicken Cap Z. Amino acid substitutions of two conserved leucines in the C-terminal actin-binding domain of the chicken β subunit resulted in significant decreases in F-actin binding activity, identifying these residues as critical for actin binding. The human CAPZB gene was mapped to chromosome 1p36.1.\",\n      \"method\": \"F-actin cosedimentation assay; site-directed mutagenesis of conserved leucine residues; chromosomal mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution (cosedimentation) combined with mutagenesis in a single rigorous study\",\n      \"pmids\": [\"7665558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CAPZB regulates actin filament length at the mitotic cortex. Loss-of-function of CAPZB (along with CFL1 and DIAPH1) altered mitotic cortex thickness, and both increasing and decreasing thickness decreased cortical tension, indicating the mitotic cortex is poised near a tension maximum. CAPZB knockdown thus modulates cell surface tension through control of cortical actin network architecture.\",\n      \"method\": \"RNAi knockdown with live-cell imaging of cortex thickness; cortical tension measurements (micropipette aspiration); computational modeling\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KD with defined cellular phenotype, quantitative tension measurements, computational model; replicated across multiple conditions\",\n      \"pmids\": [\"28530659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CAPZB (CAPZ) restrains actomyosin contractility by capping actin barbed ends: Capzb conditional knockout in mouse hepatocytes led to altered stress fiber and focal adhesion dynamics, enhanced myosin activity, increased traction forces, and increased liver stiffness. This mechanical change activated YAP in parallel to the Hippo pathway, causing hepatocyte proliferation and liver overgrowth. ROCK inhibition or Yap1 deletion reversed these phenotypes, placing CAPZB upstream of mechanotransduction-driven YAP activation.\",\n      \"method\": \"Conditional knockout mouse (Capzb flox); traction force microscopy; atomic force microscopy (liver stiffness); YAP localization/activity assays; genetic epistasis with ROCK inhibitor (fasudil) and Yap1 deletion\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO in vivo and in vitro with multiple orthogonal methods (traction forces, stiffness, genetic epistasis) establishing pathway position\",\n      \"pmids\": [\"30878582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CAPZB is required for stereocilia length and width regulation in cochlear hair cells. CAPZB is present at ~100 copies per stereocilium and concentrates at stereocilia tips as development progresses. Hair-cell-specific Capzb deletion (Atoh1-Cre) eliminated auditory and vestibular function; Capzb-null stereocilia initially developed normally but then shortened and disappeared, with concomitant decrease in width. Overexpression of CAPZB2 prevented normal elongation and caused irregular widening, indicating capping protein participates in stereocilia widening by preventing newly elongating actin filaments from depolymerizing.\",\n      \"method\": \"Hair-cell-specific conditional knockout (Atoh1-Cre); in utero electroporation overexpression; phalloidin labeling with quantitative imaging of stereocilia dimensions; auditory brainstem response and vestibular assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO and overexpression with quantitative morphological and functional readouts in a single rigorous study\",\n      \"pmids\": [\"28899994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CAPZB controls spindle orientation independently of its classical role in actin cytoskeleton. RNAi depletion of CAPZB in a micropatterning/Gαi-induction cell model disrupted spindle orientation. Mechanistically, CAPZB regulates the assembly, stability, and motor activity of the dynein/dynactin complex at the cell cortex and controls mitotic microtubule dynamics. In vivo, CAPZB controls planar divisions in the developing neuroepithelium.\",\n      \"method\": \"RNAi screen in micropatterned cells with localized Gαi recruitment; live imaging of spindle orientation; dynein/dynactin complex analysis; in vivo neuroepithelium assay\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined cellular phenotype by RNAi with in vivo validation, but mechanistic detail on dynein/dynactin derived from single lab study\",\n      \"pmids\": [\"28803871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CAPZB regulates cell morphology, differentiation, and neural crest migration in craniofacial morphogenesis. In zebrafish capzb−/− mutants, loss of capzb disrupted neural crest cell migration, caused cleft phenotype by loss of the median cell population, and disrupted trunk neural crest migration (melanophore disorganization). capzb was required for differentiation of both myogenic stem cells and neural crest cells. capzb overexpression caused embryonic lethality, indicating dosage sensitivity.\",\n      \"method\": \"Zebrafish capzb null mutant and overexpression; live imaging of neural crest migration; whole-mount in situ hybridization; human case with de novo balanced chromosomal translocation disrupting CAPZB\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function in zebrafish with defined cellular phenotypes; supported by human genetic evidence\",\n      \"pmids\": [\"26758871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In fission yeast, TORC2-dependent phosphorylation of the actin-capping protein Acp1 (equivalent of mammalian CAPZα) controls cytokinetic actomyosin ring (CAR) stability and modulates Acp1-Acp2 (CAPZA-CAPZB) heterodimer formation; disruption of TORC2 or this phosphorylation impairs CAR morphology and constriction.\",\n      \"method\": \"Fission yeast genetics; co-immunoprecipitation; phosphorylation analysis; live-cell imaging of CAR dynamics\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and biochemical evidence in yeast ortholog system; directly demonstrates CAPZA-CAPZB heterodimer formation regulated by phosphorylation\",\n      \"pmids\": [\"27206859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CAPZB knockdown in epithelioid sarcoma cells inhibited cell growth, invasion, and migration. Proteomic profiling after CAPZB silencing identified INI1 (SWI/SNF complex) as a potential upstream regulator of CAPZB; silencing CAPZB decreased INI1 protein expression in INI1-positive cells, while INI1 induction in INI1-deficient cells increased CAPZB mRNA.\",\n      \"method\": \"siRNA knockdown in EpiS cell lines; invasion/migration assays; iTRAQ quantitative proteomics; INI1 overexpression; IPA pathway analysis\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined phenotypic readouts and proteomic pathway analysis; single lab study\",\n      \"pmids\": [\"26965049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"A spermatid-specific CAPZ heterodimer (CAPZA3/CAPZB variant isoform) is essential for F-actin network organization during spermiation. In repro32 mice with a missense mutation in Capza3, CAPZB variant isoform localization was altered concurrent with disruption of the F-actin network, failure to shed excess cytoplasm, and disorganization of the sperm flagellum midpiece. This established that the CAPZA3/CAPZB heterodimer regulates F-actin dynamics required for cytoplasm removal and midpiece integrity.\",\n      \"method\": \"ENU-induced mutant mouse (repro32); candidate-gene sequencing; immunofluorescence localization of CAPZB variant; F-actin staining; sperm morphology and motility analysis\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with localization and structural readouts; single lab, orthologous mouse model\",\n      \"pmids\": [\"19341723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CAPZB localizes to stereocilia tips at row 2 of cochlear inner hair cells in a mechanotransduction-dependent manner. In transduction mutants (Tmc1/Tmc2 or Tmie knockouts), CAPZB and its partner TWF2 failed to concentrate at row 2 tips. Block of transduction channels also redistributed CAPZB from row 2 tips, demonstrating that mechanotransduction activity specifies CAPZB subcellular localization at stereocilia.\",\n      \"method\": \"Mouse cochlear hair cell immunofluorescence; Tmc1/Tmc2 and Tmie knockout models; transduction channel blocker treatment; quantitative confocal imaging\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with genetic and pharmacological perturbation linked to functional (transduction) state; single lab\",\n      \"pmids\": [\"31902726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Vasopressin treatment of kidney collecting duct cells caused significant changes in abundance of CAPZB at the apical plasma membrane. CAPZB was identified as one of five F-actin end-binding proteins involved in vasopressin-induced F-actin reorganization, which is required for aquaporin-2 apical trafficking and increased water permeability.\",\n      \"method\": \"Stable isotope quantitative proteomics (SILAC); surface biotinylation; live-cell F-actin imaging; vasopressin stimulation of mouse cortical collecting duct cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — CAPZB identified as a regulated component by proteomics; no direct functional perturbation of CAPZB itself was performed\",\n      \"pmids\": [\"24085853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Quaking (QK) promotes inclusion of Capzb exon 9 in opposition to repression by polypyrimidine tract-binding protein (PTB) during muscle cell differentiation. Mass spectrometry of proteins selected by the Capzb exon 9 intron (containing ACUAA STAR motifs) via RNA affinity chromatography identified QK as a splicing regulator of this exon, establishing a mechanism for muscle-specific alternative splicing of CAPZB.\",\n      \"method\": \"RNA affinity chromatography with mass spectrometry; QK depletion by RNAi; RT-PCR splicing assays; myoblast-to-myotube differentiation model\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA affinity chromatography plus functional RNAi knockdown with splicing readout; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"23525800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ALIX recruits actin-capping proteins CAPZA1/CAPZB to prevent branched filamentous actin (F-actin) accumulation around multivesicular bodies (MVBs), enabling MVB trafficking to the cell periphery for exosome secretion. PTPN23 (competitor of ALIX for syntenin binding) does not recruit CAPZA1/CAPZB. This ALIX–CAPZA1/CAPZB mechanism is required for the pro-tumorigenic exosome secretion pathway.\",\n      \"method\": \"Co-immunoprecipitation; genetic perturbation (PTPN23 knockout, ALIX depletion); F-actin visualization around MVBs; exosome secretion assays in mouse and human cancer cells\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and functional genetic perturbation with defined cellular readout; single lab\",\n      \"pmids\": [\"40185104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"HDAC8 desuccinylates CAPZB at lysine residues K57, K95, and K235. CAPZB regulates cytoskeletal remodeling and fibroblast-to-myofibroblast differentiation by capping the barbed end of F-actin. Desuccinylation (removal of succinyl groups) inhibits CAPZB function and promotes cytoskeletal remodeling; mutation of the modification sites confirmed that succinylation inhibits CAPZB activity. HDAC8 physically interacts with CAPZB and its pro-fibrotic role as a desuccinylase was verified in vitro and in vivo.\",\n      \"method\": \"Mass spectrometry identification of succinylation sites; site-directed mutagenesis of K57/K95/K235; gain- and loss-of-function in fibroblasts and in vivo mouse model; Co-IP of HDAC8 with CAPZB; F-actin capping and cytoskeletal assays\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — identification of PTM sites by MS, mutagenesis confirming functional relevance, identification of writer enzyme (HDAC8) by Co-IP, in vitro and in vivo validation in single study\",\n      \"pmids\": [\"42050207\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CAPZB encodes the β subunit of the heterodimeric F-actin barbed-end capping protein (Cap Z), which physically blocks actin polymerization at barbed ends via C-terminal residues; it restrains actomyosin contractility and cortical tension by limiting actin filament length, localizes to actin-rich structures (stereocilia tips, cortex, MVBs) where it controls dimensions and dynamics, participates in spindle orientation by regulating dynein/dynactin at the cell cortex, is recruited to MVBs by ALIX to enable exosome secretion, and is regulated post-translationally by HDAC8-mediated desuccinylation at K57/K95/K235, with muscle-specific isoforms generated by QK/PTB-controlled alternative splicing of exon 9.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CAPZB encodes the β subunit of the heterodimeric F-actin barbed-end capping protein (CapZ), which binds F-actin through C-terminal residues—two conserved leucines being critical for binding activity—and pairs with a CAPZA α subunit to cap filament barbed ends and thereby set actin filament length [#0, #6]. By limiting barbed-end elongation, CAPZB controls the architecture and mechanics of actin networks: it tunes mitotic cortex thickness and cortical tension [#1], and restrains actomyosin contractility such that its loss in hepatocytes raises traction forces and tissue stiffness, activating YAP-driven proliferation through ROCK-dependent mechanotransduction [#2]. This length-control function underlies its roles in specialized actin-based structures, including cochlear hair-cell stereocilia, where CAPZB concentrates at tips in a mechanotransduction-dependent manner together with TWF2 and is required to maintain stereocilia length and width [#3, #9]. CAPZB also acts beyond bulk actin regulation: it controls mitotic spindle orientation by regulating dynein/dynactin assembly and motor activity at the cell cortex and governs planar divisions in the developing neuroepithelium [#4], and it is recruited by ALIX to multivesicular bodies to prevent branched F-actin accumulation, enabling MVB trafficking and exosome secretion [#12]. CAPZB is required for neural crest migration and craniofacial morphogenesis, with a human balanced translocation disrupting the gene [#5], and its activity is regulated post-translationally by HDAC8-mediated desuccinylation at K57/K95/K235, with muscle-specific isoforms generated by QK/PTB-controlled alternative splicing of exon 9 [#13, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established that human CAPZB is a functional F-actin capping subunit and pinpointed the C-terminal residues responsible for actin binding, defining the molecular basis of its activity.\",\n      \"evidence\": \"F-actin cosedimentation and site-directed mutagenesis of conserved leucines; chromosomal mapping to 1p36.1\",\n      \"pmids\": [\"7665558\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address regulation of capping in cells\", \"Heterodimer assembly with CAPZA not examined in this study\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed that a tissue-specific CAPZ heterodimer organizes F-actin in a developmental context, extending CAPZB function to spermiation.\",\n      \"evidence\": \"ENU mutant mouse (repro32) with Capza3 missense mutation; CAPZB variant localization, F-actin staining, sperm morphology\",\n      \"pmids\": [\"19341723\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Effect is via the CAPZA3 partner, not CAPZB itself\", \"Single orthologous mouse model\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified how muscle-specific CAPZB isoforms are generated, defining QK and PTB as antagonistic splicing regulators of exon 9.\",\n      \"evidence\": \"RNA affinity chromatography/MS, QK RNAi, RT-PCR splicing assays in myoblast differentiation\",\n      \"pmids\": [\"23525800\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the two isoforms on capping activity not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Implicated CAPZB in regulated apical F-actin reorganization downstream of vasopressin, linking it to membrane trafficking.\",\n      \"evidence\": \"SILAC proteomics, surface biotinylation, vasopressin stimulation of collecting duct cells\",\n      \"pmids\": [\"24085853\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct functional perturbation of CAPZB performed\", \"Correlative proteomic association only\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed a moonlighting role for CAPZB in spindle orientation through regulation of cortical dynein/dynactin, distinct from its bulk actin function.\",\n      \"evidence\": \"RNAi in micropatterned Gαi-induction cells, spindle orientation imaging, dynein/dynactin analysis, in vivo neuroepithelium\",\n      \"pmids\": [\"28803871\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of dynein/dynactin regulation derived from single lab\", \"Direct biochemical link to dynein/dynactin not established\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated organismal requirements for CAPZB in neural crest migration, differentiation, and craniofacial development, with human genetic support.\",\n      \"evidence\": \"Zebrafish capzb null and overexpression, neural crest imaging, in situ hybridization, human translocation case\",\n      \"pmids\": [\"26758871\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Dosage sensitivity mechanism unresolved\", \"Human evidence limited to a single translocation case\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linked CAPZB to tumor cell invasion and placed it within an INI1/SWI-SNF regulatory relationship in epithelioid sarcoma.\",\n      \"evidence\": \"siRNA knockdown, invasion/migration assays, iTRAQ proteomics, INI1 induction in EpiS cells\",\n      \"pmids\": [\"26965049\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"INI1-CAPZB regulation is correlative\", \"Single lab and cell-line context\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed that CAPZA-CAPZB heterodimer formation and capping function are controlled by TORC2-dependent phosphorylation, establishing regulated heterodimer assembly.\",\n      \"evidence\": \"Fission yeast genetics, Co-IP, phosphorylation analysis, live imaging of cytokinetic actomyosin ring\",\n      \"pmids\": [\"27206859\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Demonstrated in yeast orthologs (Acp1/Acp2)\", \"Conservation of TORC2 control in mammalian CAPZB not tested here\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Quantified how CAPZB tunes mitotic cortex architecture and cortical tension, showing the cortex is poised near a tension maximum.\",\n      \"evidence\": \"RNAi knockdown, live imaging of cortex thickness, micropipette aspiration tension measurement, computational modeling\",\n      \"pmids\": [\"28530659\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not separate CAPZB-specific from general capping effects\", \"Downstream signaling consequences not examined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined CAPZB as essential for stereocilia dimension control and hearing/balance, showing capping prevents depolymerization of newly elongated filaments.\",\n      \"evidence\": \"Atoh1-Cre conditional KO, in utero electroporation overexpression, quantitative phalloidin imaging, ABR and vestibular assays\",\n      \"pmids\": [\"28899994\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular partners at stereocilia tips not yet defined in this study\", \"Width-control mechanism inferred from morphology\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established CAPZB upstream of mechanotransduction-driven YAP activation, linking actin capping to tissue stiffness and organ growth.\",\n      \"evidence\": \"Capzb conditional KO mouse, traction force and atomic force microscopy, YAP assays, epistasis with ROCK inhibitor and Yap1 deletion\",\n      \"pmids\": [\"30878582\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular coupling between capping loss and YAP not fully mapped\", \"Tissue-specificity beyond hepatocytes not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed that mechanotransduction activity itself specifies CAPZB subcellular localization at stereocilia row 2 tips, alongside TWF2.\",\n      \"evidence\": \"Cochlear hair cell immunofluorescence, Tmc1/Tmc2 and Tmie KO models, channel blocker, confocal imaging\",\n      \"pmids\": [\"31902726\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signal coupling transduction to CAPZB targeting unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified ALIX as the recruiter of CAPZA1/CAPZB to MVBs, defining a capping-dependent mechanism enabling exosome secretion.\",\n      \"evidence\": \"Co-IP, PTPN23 KO and ALIX depletion, F-actin imaging around MVBs, exosome secretion assays in cancer cells\",\n      \"pmids\": [\"40185104\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of ALIX-CAPZ interaction not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined succinylation as a post-translational switch on CAPZB and HDAC8 as the desuccinylase, linking CAPZB regulation to fibroblast differentiation.\",\n      \"evidence\": \"MS site identification, K57/K95/K235 mutagenesis, gain/loss-of-function in fibroblasts and mouse model, HDAC8-CAPZB Co-IP, capping assays\",\n      \"pmids\": [\"42050207\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Succinyl writer enzyme not identified\", \"Generality across cell types beyond fibroblasts not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CAPZB switches between bulk cortical capping, structure-specific localization (stereocilia tips, MVBs), and its non-canonical dynein/dynactin role remains unresolved at the mechanistic level.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of mammalian CAPZA-CAPZB heterodimer in the corpus\", \"Recruitment logic to distinct subcellular sites not unified\", \"Direct biochemical mechanism of dynein/dynactin regulation undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 1, 3, 13]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2, 3, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 2, 10]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 4]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 5]}\n    ],\n    \"complexes\": [\"CapZ (F-actin capping protein heterodimer)\"],\n    \"partners\": [\"CAPZA1\", \"CAPZA3\", \"ALIX\", \"TWF2\", \"HDAC8\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}