{"gene":"CLTCL1","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":1996,"finding":"CLTCL1 (CLH-22/CHC22) encodes a second human clathrin heavy chain of 1640 amino acids, localized to chromosome 22q11, with 84.7% amino acid identity to CHC17; alternative splicing of a 171 bp exon near the C-terminus was observed, overlapping the putative light-chain binding domain and adjacent to the trimerization region, suggesting alternative splicing may regulate light-chain binding or trimerization.","method":"cDNA cloning, sequencing, Northern blot analysis, sequence comparison","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — full cDNA characterization with structural inference, single lab, multiple orthogonal methods (cloning, Northern, sequence analysis)","pmids":["8733129"],"is_preprint":false},{"year":1996,"finding":"CLTCL1 (CLTCL) is selectively expressed in adult skeletal muscle and shows alternative splicing near the carboxyl terminus in a region overlapping the putative light-chain binding domain adjacent to the heavy chain trimerization region.","method":"Northern blot analysis, cDNA cloning and sequencing","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct cloning and sequencing with expression profiling, single lab, two orthogonal methods","pmids":["8844170"],"is_preprint":false},{"year":1997,"finding":"A balanced (21;22)(p12;q11) translocation interrupts the 3' coding region of CLTCL1, producing a truncated transcript and resulting in a patient with some features of DiGeorge syndrome/velocardiofacial syndrome, establishing that CLTCL1 haploinsufficiency contributes to this phenotype.","method":"Breakpoint cloning, Northern blot of truncated transcript","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct molecular cloning of breakpoint and truncated transcript, single case, single lab","pmids":["9147638"],"is_preprint":false},{"year":2000,"finding":"CLTCL1 fuses to ALK kinase in a variant chromosomal translocation in anaplastic lymphoma, generating a CLTCL-ALK fusion protein (~250 kDa) that localizes to clathrin-coated vesicles and is constitutively autophosphorylated, demonstrating that the CLTCL portion mediates membrane targeting and contributes an active promoter.","method":"cDNA cloning of fusion gene, immunostaining for ALK localization, in vitro kinase assay for autophosphorylation","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro kinase assay plus localization studies, single lab, two orthogonal methods","pmids":["10807789"],"is_preprint":false},{"year":2004,"finding":"CHC22 binds sorting nexin 5 (SNX5) through a coiled-coil domain present in both CHC22 and SNX5 but absent in CHC17; this domain coincides with the region on CHC17 that binds the regulatory light-chain subunit, providing a mechanism for the distinct functions of CHC22 relative to CHC17 in membrane traffic. CHC22 is concentrated at neuromuscular and myotendinous junctions in mature muscle, and its expression is increased during myoblast differentiation and muscle regeneration with a similar time course as embryonic myosin.","method":"Co-immunoprecipitation, subcellular fractionation, immunofluorescence/localization, domain mapping","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding experiments and domain mapping plus localization, single lab, multiple orthogonal methods","pmids":["15133132"],"is_preprint":false},{"year":2009,"finding":"CHC22 is required for formation of insulin-responsive GLUT4 storage compartments in human skeletal muscle and adipocytes; tissue-specific transgenic expression of CHC22 in mice (which normally lack it) caused aberrant localization of GLUT4 transport pathway components and diabetic features, establishing a species-restricted role for CHC22 in insulin-regulated GLUT4 trafficking.","method":"CHC22 knockdown in human cells, CHC22 transgenic mouse model, GLUT4 localization assays, glucose tolerance testing","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (knockdown, transgenic mouse, glucose tolerance), replicated across cell types and in vivo","pmids":["19478182"],"is_preprint":false},{"year":2010,"finding":"CHC22 is required for retrograde trafficking of certain cargo molecules from endosomes to the trans-Golgi network (TGN) via a pathway distinct from CHC17 and retromer; in muscle cells, depletion of either CHC22 or syntaxin 10 (a species-restricted SNARE not expressed in mice) impairs GLUT4 targeting, placing retrograde endosome-TGN transport as a critical step in GLUT4 trafficking. CHC22 is ~8-fold less abundant than CHC17 in muscle, and CHC22 and CHC17 function independently in both nonmuscle and muscle cells.","method":"siRNA knockdown, cargo trafficking assays, subcellular fractionation, immunofluorescence","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple cargo assays, epistasis via double knockdown with syntaxin 10, clean loss-of-function with defined cellular phenotype","pmids":["20065094"],"is_preprint":false},{"year":2013,"finding":"CHC22 participates in muscle regeneration: GLUT4 and VAMP2 are elevated in regenerating human myofibers in parallel with CHC22; CHC22 transgenic mice show delayed muscle regeneration after cardiotoxin injury and myoblasts from these mice fail to proliferate in response to glucose, and CHC22 expression causes a fiber-type switch from oxidative to glycolytic metabolism.","method":"Human biopsy immunostaining, CHC22 transgenic mouse cardiotoxin injury model, myoblast proliferation assay, fiber-type analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transgenic mouse model with defined phenotype and human tissue correlation, single lab, multiple orthogonal methods","pmids":["24204966"],"is_preprint":false},{"year":2017,"finding":"CHC22 forms a triskelion and assembles into latticed vesicle coats morphologically similar to CHC17 coats, but CHC22-coated vesicles are distinct: the CHC22 coat is more stable to pH change, is not disassembled by the Hsc70/auxilin uncoating machinery that disassembles CHC17 coats, CHC22 and CHC17 are differentially recruited to membranes by adaptors, and CHC22 does not support vesicle formation or transferrin endocytosis at the plasma membrane.","method":"In vitro coat assembly/disassembly assays, electron microscopy of vesicles, endocytosis assays, adaptor recruitment assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of coat assembly/disassembly, EM structural characterization, functional endocytosis assays, single lab with multiple orthogonal methods","pmids":["29097553"],"is_preprint":false},{"year":2019,"finding":"A common human CLTCL1 allelic variant encoding valine at position 1316 (CHC22-V1316), more frequent in farming populations, shows different cellular dynamics than M1316-CHC22 and is less effective at controlling GLUT4 membrane traffic, altering the insulin-regulated GLUT4 response; population genetic analysis reveals strong purifying selection on CLTCL1 in vertebrates retaining the gene.","method":"Population genetics/phylogenetics, functional cellular assays of GLUT4 trafficking comparing allotypes, live-cell imaging of CHC22 dynamics","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional cellular assay comparing allotypes plus evolutionary analysis, single lab, two orthogonal methods","pmids":["31159924"],"is_preprint":false},{"year":2020,"finding":"CHC22 localizes to the ERGIC (ER-to-Golgi intermediate compartment) and functions in transport from the ERGIC to form the GLUT4 storage compartment (GSC), acting upstream of the previously described retrograde endosomal sorting step. CHC22 forms a complex with ERGIC tether p115, GLUT4, and sortilin; downregulation of p115 or CHC22 (but not GM130 or sortilin) abrogates insulin-responsive GLUT4 release. CHC22's ERGIC role is further demonstrated by its essential function in forming the Legionella pneumophila replication vacuole, which requires ERGIC-derived membrane.","method":"siRNA knockdown, co-immunoprecipitation, RUSH (retention using selective hooks) secretory pathway tracing, Legionella infection assay, immunofluorescence localization","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods including co-IP, pulse-chase trafficking, bacterial infection functional assay, and epistatic knockdowns defining pathway order","pmids":["31863584"],"is_preprint":false},{"year":2024,"finding":"CHC22 is recruited to ERGIC membranes via a bipartite two-site interaction: (1) the C-terminal trimerization domain of CHC22 interacts with SNX5 (and functionally redundant SNX6), which also binds the ERGIC tether p115; (2) an isoform-specific patch in the CHC22 N-terminal domain separately mediates direct binding to p115. Both interactions are independently required for CHC22 targeting to ERGIC membranes and for directing GLUT4 to the GSC; interference with either interaction inhibits GLUT4 targeting.","method":"Co-immunoprecipitation, domain mutagenesis/deletion mapping, siRNA knockdown of SNX5/SNX6, GLUT4 trafficking assays, immunofluorescence localization","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP with domain mutagenesis, epistatic knockdowns, functional GLUT4 trafficking readout, single lab with multiple orthogonal methods","pmids":["39160272"],"is_preprint":false}],"current_model":"CHC22 (CLTCL1) is a human-enriched clathrin heavy-chain isoform that forms triskelion-based vesicle coats with distinct biochemical properties from ubiquitous CHC17 (more pH-stable, resistant to Hsc70/auxilin uncoating, differently regulated by adaptors); it is recruited to ERGIC membranes via a bipartite mechanism requiring both its C-terminal trimerization domain binding SNX5/SNX6 (which also contacts ERGIC tether p115) and an isoform-specific N-terminal patch that directly binds p115, enabling CHC22 to mediate a Golgi-bypass route that sequesters GLUT4 into an intracellular storage compartment from which insulin can mobilize it to the plasma membrane, with a secondary role in retrograde endosome-to-TGN sorting (requiring syntaxin 10) that recaptures GLUT4 after endocytosis, and additional functions during skeletal muscle development, regeneration, and at neuromuscular junctions."},"narrative":{"mechanistic_narrative":"CLTCL1 encodes CHC22, a human-enriched clathrin heavy-chain isoform that builds triskelion-based vesicle coats biochemically distinct from the ubiquitous CHC17: the CHC22 coat is more pH-stable, is not disassembled by the Hsc70/auxilin uncoating machinery, is differentially recruited by adaptors, and does not support plasma-membrane endocytosis [PMID:29097553]. Its central cellular role is the biogenesis of the insulin-responsive GLUT4 storage compartment in human skeletal muscle and adipocytes, a species-restricted function: depletion impairs GLUT4 sequestration, and ectopic expression in mice (which lack the gene) mislocalizes GLUT4 pathway components and produces diabetic features [PMID:19478182]. CHC22 acts at the ER-to-Golgi intermediate compartment (ERGIC), where it forms a complex with the tether p115, GLUT4, and sortilin to route GLUT4 into the storage compartment, upstream of a separate retrograde endosome-to-TGN recapture step that requires syntaxin 10 [PMID:20065094, PMID:31863584]. Recruitment to ERGIC membranes is bipartite, requiring both the C-terminal trimerization domain binding SNX5/SNX6 (which itself contacts p115) and an isoform-specific N-terminal patch that binds p115 directly; disruption of either interaction blocks GLUT4 targeting [PMID:39160272, PMID:15133132]. A common coding variant (V1316) alters CHC22 dynamics and is less effective at controlling GLUT4 traffic, and CLTCL1 is under strong purifying selection in vertebrates retaining it [PMID:31159924]. CHC22 is enriched at neuromuscular and myotendinous junctions and is upregulated during myoblast differentiation and muscle regeneration, where it influences fiber-type metabolism [PMID:15133132, PMID:24204966]. A balanced translocation truncating CLTCL1 produces features of DiGeorge/velocardiofacial syndrome, implicating haploinsufficiency in that phenotype [PMID:9147638].","teleology":[{"year":1996,"claim":"Establishing that humans possess a second clathrin heavy-chain gene distinct from the canonical CHC17 raised the question of whether a paralog with a specialized function exists.","evidence":"cDNA cloning, sequencing, and Northern analysis of a 1640-aa heavy chain on chromosome 22q11 with 84.7% identity to CHC17 and skeletal-muscle-selective expression","pmids":["8733129","8844170"],"confidence":"Medium","gaps":["no functional distinction from CHC17 established at this stage","biochemical consequence of the C-terminal alternative splicing untested","binding partners unknown"]},{"year":1997,"claim":"Linking CLTCL1 disruption to a developmental syndrome tested whether the gene has a dosage-sensitive role in vivo.","evidence":"Breakpoint cloning of a balanced (21;22) translocation truncating CLTCL1 and Northern detection of the truncated transcript in a patient with DiGeorge/velocardiofacial features","pmids":["9147638"],"confidence":"Medium","gaps":["single case, causality vs contiguous-gene effects not resolved","molecular mechanism connecting truncation to phenotype unknown"]},{"year":2000,"claim":"An ALK fusion to CLTCL1 in anaplastic lymphoma showed that the CHC22 portion confers membrane targeting, indirectly demonstrating its vesicle-associated localization.","evidence":"cDNA cloning of a CLTCL-ALK fusion, immunostaining localizing the fusion to clathrin-coated vesicles, and in vitro kinase autophosphorylation assay","pmids":["10807789"],"confidence":"Medium","gaps":["informs only the targeting/oligomerization region, not endogenous CHC22 function","no normal-cell trafficking readout"]},{"year":2004,"claim":"Identifying SNX5 as a CHC22-specific partner via a domain absent in CHC17 provided the first molecular basis for divergent CHC22 function.","evidence":"Co-immunoprecipitation, domain mapping, fractionation, and immunofluorescence showing a coiled-coil CHC22–SNX5 interaction and junctional/regeneration-linked muscle expression","pmids":["15133132"],"confidence":"Medium","gaps":["downstream trafficking pathway not yet defined","cargo not identified at this stage"]},{"year":2009,"claim":"Demonstrating that CHC22 is required to build insulin-responsive GLUT4 storage compartments defined its principal physiological cargo and a species-restricted metabolic role.","evidence":"CHC22 knockdown in human cells, CHC22 transgenic mice with GLUT4 mislocalization and diabetic features, and glucose tolerance testing","pmids":["19478182"],"confidence":"High","gaps":["step in the GLUT4 itinerary controlled by CHC22 not yet localized","direct molecular interactions with GLUT4 machinery undefined"]},{"year":2010,"claim":"Placing CHC22 in a retrograde endosome-to-TGN route distinct from CHC17 and retromer identified a specific trafficking step underlying GLUT4 targeting.","evidence":"siRNA knockdown of CHC22 and syntaxin 10, cargo trafficking assays, and fractionation showing independent CHC22/CHC17 function","pmids":["20065094"],"confidence":"High","gaps":["whether retrograde sorting was the primary or a recapture step unresolved at the time","coat assembly properties not yet characterized"]},{"year":2017,"claim":"Reconstituting CHC22 coats biochemically distinguished it from CHC17, explaining how a near-identical heavy chain forms a functionally separate coat.","evidence":"In vitro coat assembly/disassembly, EM of vesicles, endocytosis assays, and adaptor recruitment assays showing pH stability, Hsc70/auxilin resistance, and absence of plasma-membrane endocytosis","pmids":["29097553"],"confidence":"High","gaps":["physiological adaptors and membrane recruitment site not defined","structural basis for uncoating resistance not solved"]},{"year":2019,"claim":"A common coding allotype affecting GLUT4 control linked CHC22 sequence variation to metabolic physiology and revealed evolutionary constraint.","evidence":"Population genetics/phylogenetics with functional cellular GLUT4 trafficking assays and live-cell imaging comparing V1316 and M1316 allotypes","pmids":["31159924"],"confidence":"Medium","gaps":["mechanistic basis for allotype dynamic differences unresolved","organismal/clinical metabolic consequences in humans not established"]},{"year":2020,"claim":"Localizing CHC22 to the ERGIC and identifying a p115–GLUT4–sortilin complex placed CHC22 at an upstream Golgi-bypass step in GSC biogenesis.","evidence":"siRNA knockdown, co-IP, RUSH secretory tracing, immunofluorescence, and a Legionella replication-vacuole assay requiring ERGIC membrane","pmids":["31863584"],"confidence":"High","gaps":["molecular mechanism of CHC22 recruitment to ERGIC not yet defined","role of sortilin in the complex not functionally required"]},{"year":2024,"claim":"Defining a bipartite two-site recruitment mechanism resolved how CHC22 is targeted to ERGIC membranes to direct GLUT4.","evidence":"Co-IP, domain mutagenesis/deletion mapping, SNX5/SNX6 knockdown, and GLUT4 trafficking assays showing both a C-terminal trimerization–SNX5/6 contact and an N-terminal isoform-specific patch binding p115 are independently required","pmids":["39160272"],"confidence":"High","gaps":["structural details of the N-terminal p115 patch not solved","regulation of recruitment by insulin signaling not addressed"]},{"year":null,"claim":"How CHC22 coat formation, ERGIC recruitment, and insulin signaling are coordinated to release GLUT4 to the plasma membrane remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["no structure of CHC22 coat or its recruitment interfaces","mechanism coupling insulin signaling to GSC mobilization undefined","basis for resistance to Hsc70/auxilin uncoating unexplained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[8]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[10,11]}],"localization":[{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[3,8]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[10,11]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[6,10]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[6,8,10]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[5,10]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[10,11]}],"complexes":["CHC22 clathrin coat","CHC22-p115-GLUT4-sortilin ERGIC complex"],"partners":["SNX5","SNX6","USO1/P115","GLUT4","SORT1","STX10"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P53675","full_name":"Clathrin heavy chain 2","aliases":["Clathrin heavy chain on chromosome 22","CLH-22"],"length_aa":1640,"mass_kda":187.0,"function":"Clathrin is the major protein of the polyhedral coat of coated pits and vesicles. Two different adapter protein complexes link the clathrin lattice either to the plasma membrane or to the trans-Golgi network (By similarity)","subcellular_location":"Cytoplasmic vesicle membrane; Membrane, coated pit","url":"https://www.uniprot.org/uniprotkb/P53675/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CLTCL1","classification":"Not Classified","n_dependent_lines":28,"n_total_lines":1208,"dependency_fraction":0.023178807947019868},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CLTA","stoichiometry":0.2},{"gene":"CLTB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CLTCL1","total_profiled":1310},"omim":[{"mim_id":"601273","title":"CLATHRIN, HEAVY POLYPEPTIDE-LIKE 1; CLTCL1","url":"https://www.omim.org/entry/601273"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"skeletal muscle","ntpm":180.9},{"tissue":"testis","ntpm":45.3},{"tissue":"tongue","ntpm":57.3}],"url":"https://www.proteinatlas.org/search/CLTCL1"},"hgnc":{"alias_symbol":["CLTD","CLH22","CHC22"],"prev_symbol":["CLTCL"]},"alphafold":{"accession":"P53675","domains":[{"cath_id":"-","chopping":"872-930","consensus_level":"medium","plddt":67.7447,"start":872,"end":930}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P53675","model_url":"https://alphafold.ebi.ac.uk/files/AF-P53675-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P53675-F1-predicted_aligned_error_v6.png","plddt_mean":77.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CLTCL1","jax_strain_url":"https://www.jax.org/strain/search?query=CLTCL1"},"sequence":{"accession":"P53675","fasta_url":"https://rest.uniprot.org/uniprotkb/P53675.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P53675/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P53675"}},"corpus_meta":[{"pmid":"10807789","id":"PMC_10807789","title":"Further demonstration of the diversity of chromosomal changes involving 2p23 in ALK-positive lymphoma: 2 cases expressing ALK kinase fused to CLTCL (clathrin chain polypeptide-like).","date":"2000","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/10807789","citation_count":166,"is_preprint":false},{"pmid":"19478182","id":"PMC_19478182","title":"A role for the CHC22 clathrin heavy-chain isoform in human glucose metabolism.","date":"2009","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/19478182","citation_count":94,"is_preprint":false},{"pmid":"8733129","id":"PMC_8733129","title":"Characterization of a second human clathrin heavy chain polypeptide gene (CLH-22) from chromosome 22q11.","date":"1996","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8733129","citation_count":52,"is_preprint":false},{"pmid":"20065094","id":"PMC_20065094","title":"The clathrin heavy chain isoform CHC22 functions in a novel endosomal sorting step.","date":"2010","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/20065094","citation_count":51,"is_preprint":false},{"pmid":"9147638","id":"PMC_9147638","title":"Disruption of the clathrin heavy chain-like gene (CLTCL) associated with features of DGS/VCFS: a balanced (21;22)(p12;q11) translocation.","date":"1997","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9147638","citation_count":41,"is_preprint":false},{"pmid":"31863584","id":"PMC_31863584","title":"CHC22 clathrin mediates traffic from early secretory compartments for human GLUT4 pathway biogenesis.","date":"2020","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/31863584","citation_count":39,"is_preprint":false},{"pmid":"15133132","id":"PMC_15133132","title":"Clathrin isoform CHC22, a component of neuromuscular and myotendinous junctions, binds sorting nexin 5 and has increased expression during myogenesis and muscle regeneration.","date":"2004","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/15133132","citation_count":38,"is_preprint":false},{"pmid":"32620516","id":"PMC_32620516","title":"Building GLUT4 Vesicles: CHC22 Clathrin's Human Touch.","date":"2020","source":"Trends in cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/32620516","citation_count":32,"is_preprint":false},{"pmid":"31159924","id":"PMC_31159924","title":"Genetic diversity of CHC22 clathrin impacts its function in glucose metabolism.","date":"2019","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/31159924","citation_count":21,"is_preprint":false},{"pmid":"8844170","id":"PMC_8844170","title":"Cloning and characterization of a novel human clathrin heavy chain gene (CLTCL).","date":"1996","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8844170","citation_count":21,"is_preprint":false},{"pmid":"29097553","id":"PMC_29097553","title":"CHC22 and CHC17 clathrins have distinct 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cLTD.","date":"2020","source":"eNeuro","url":"https://pubmed.ncbi.nlm.nih.gov/32205379","citation_count":9,"is_preprint":false},{"pmid":"39160272","id":"PMC_39160272","title":"CHC22 clathrin recruitment to the early secretory pathway requires two-site interaction with SNX5 and p115.","date":"2024","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/39160272","citation_count":3,"is_preprint":false},{"pmid":"39245064","id":"PMC_39245064","title":"Efficient glycyrrhetinic acid biomanufacturing through protein engineering and dual-GUS combination strategy with novel β-glucuronidase from Aspergillus calidoustus CLH-22.","date":"2024","source":"Bioresource technology","url":"https://pubmed.ncbi.nlm.nih.gov/39245064","citation_count":3,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.05.13.653827","title":"Perisynaptic astroglial response to  <i>in vivo</i>  long-term potentiation and concurrent long-term depression in the hippocampal dentate 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suggesting alternative splicing may regulate light-chain binding or trimerization.\",\n      \"method\": \"cDNA cloning, sequencing, Northern blot analysis, sequence comparison\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — full cDNA characterization with structural inference, single lab, multiple orthogonal methods (cloning, Northern, sequence analysis)\",\n      \"pmids\": [\"8733129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"CLTCL1 (CLTCL) is selectively expressed in adult skeletal muscle and shows alternative splicing near the carboxyl terminus in a region overlapping the putative light-chain binding domain adjacent to the heavy chain trimerization region.\",\n      \"method\": \"Northern blot analysis, cDNA cloning and sequencing\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct cloning and sequencing with expression profiling, single lab, two orthogonal methods\",\n      \"pmids\": [\"8844170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"A balanced (21;22)(p12;q11) translocation interrupts the 3' coding region of CLTCL1, producing a truncated transcript and resulting in a patient with some features of DiGeorge syndrome/velocardiofacial syndrome, establishing that CLTCL1 haploinsufficiency contributes to this phenotype.\",\n      \"method\": \"Breakpoint cloning, Northern blot of truncated transcript\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct molecular cloning of breakpoint and truncated transcript, single case, single lab\",\n      \"pmids\": [\"9147638\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"CLTCL1 fuses to ALK kinase in a variant chromosomal translocation in anaplastic lymphoma, generating a CLTCL-ALK fusion protein (~250 kDa) that localizes to clathrin-coated vesicles and is constitutively autophosphorylated, demonstrating that the CLTCL portion mediates membrane targeting and contributes an active promoter.\",\n      \"method\": \"cDNA cloning of fusion gene, immunostaining for ALK localization, in vitro kinase assay for autophosphorylation\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase assay plus localization studies, single lab, two orthogonal methods\",\n      \"pmids\": [\"10807789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CHC22 binds sorting nexin 5 (SNX5) through a coiled-coil domain present in both CHC22 and SNX5 but absent in CHC17; this domain coincides with the region on CHC17 that binds the regulatory light-chain subunit, providing a mechanism for the distinct functions of CHC22 relative to CHC17 in membrane traffic. CHC22 is concentrated at neuromuscular and myotendinous junctions in mature muscle, and its expression is increased during myoblast differentiation and muscle regeneration with a similar time course as embryonic myosin.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, immunofluorescence/localization, domain mapping\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding experiments and domain mapping plus localization, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"15133132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CHC22 is required for formation of insulin-responsive GLUT4 storage compartments in human skeletal muscle and adipocytes; tissue-specific transgenic expression of CHC22 in mice (which normally lack it) caused aberrant localization of GLUT4 transport pathway components and diabetic features, establishing a species-restricted role for CHC22 in insulin-regulated GLUT4 trafficking.\",\n      \"method\": \"CHC22 knockdown in human cells, CHC22 transgenic mouse model, GLUT4 localization assays, glucose tolerance testing\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (knockdown, transgenic mouse, glucose tolerance), replicated across cell types and in vivo\",\n      \"pmids\": [\"19478182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CHC22 is required for retrograde trafficking of certain cargo molecules from endosomes to the trans-Golgi network (TGN) via a pathway distinct from CHC17 and retromer; in muscle cells, depletion of either CHC22 or syntaxin 10 (a species-restricted SNARE not expressed in mice) impairs GLUT4 targeting, placing retrograde endosome-TGN transport as a critical step in GLUT4 trafficking. CHC22 is ~8-fold less abundant than CHC17 in muscle, and CHC22 and CHC17 function independently in both nonmuscle and muscle cells.\",\n      \"method\": \"siRNA knockdown, cargo trafficking assays, subcellular fractionation, immunofluorescence\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple cargo assays, epistasis via double knockdown with syntaxin 10, clean loss-of-function with defined cellular phenotype\",\n      \"pmids\": [\"20065094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CHC22 participates in muscle regeneration: GLUT4 and VAMP2 are elevated in regenerating human myofibers in parallel with CHC22; CHC22 transgenic mice show delayed muscle regeneration after cardiotoxin injury and myoblasts from these mice fail to proliferate in response to glucose, and CHC22 expression causes a fiber-type switch from oxidative to glycolytic metabolism.\",\n      \"method\": \"Human biopsy immunostaining, CHC22 transgenic mouse cardiotoxin injury model, myoblast proliferation assay, fiber-type analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transgenic mouse model with defined phenotype and human tissue correlation, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"24204966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CHC22 forms a triskelion and assembles into latticed vesicle coats morphologically similar to CHC17 coats, but CHC22-coated vesicles are distinct: the CHC22 coat is more stable to pH change, is not disassembled by the Hsc70/auxilin uncoating machinery that disassembles CHC17 coats, CHC22 and CHC17 are differentially recruited to membranes by adaptors, and CHC22 does not support vesicle formation or transferrin endocytosis at the plasma membrane.\",\n      \"method\": \"In vitro coat assembly/disassembly assays, electron microscopy of vesicles, endocytosis assays, adaptor recruitment assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of coat assembly/disassembly, EM structural characterization, functional endocytosis assays, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"29097553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A common human CLTCL1 allelic variant encoding valine at position 1316 (CHC22-V1316), more frequent in farming populations, shows different cellular dynamics than M1316-CHC22 and is less effective at controlling GLUT4 membrane traffic, altering the insulin-regulated GLUT4 response; population genetic analysis reveals strong purifying selection on CLTCL1 in vertebrates retaining the gene.\",\n      \"method\": \"Population genetics/phylogenetics, functional cellular assays of GLUT4 trafficking comparing allotypes, live-cell imaging of CHC22 dynamics\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional cellular assay comparing allotypes plus evolutionary analysis, single lab, two orthogonal methods\",\n      \"pmids\": [\"31159924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CHC22 localizes to the ERGIC (ER-to-Golgi intermediate compartment) and functions in transport from the ERGIC to form the GLUT4 storage compartment (GSC), acting upstream of the previously described retrograde endosomal sorting step. CHC22 forms a complex with ERGIC tether p115, GLUT4, and sortilin; downregulation of p115 or CHC22 (but not GM130 or sortilin) abrogates insulin-responsive GLUT4 release. CHC22's ERGIC role is further demonstrated by its essential function in forming the Legionella pneumophila replication vacuole, which requires ERGIC-derived membrane.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation, RUSH (retention using selective hooks) secretory pathway tracing, Legionella infection assay, immunofluorescence localization\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods including co-IP, pulse-chase trafficking, bacterial infection functional assay, and epistatic knockdowns defining pathway order\",\n      \"pmids\": [\"31863584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CHC22 is recruited to ERGIC membranes via a bipartite two-site interaction: (1) the C-terminal trimerization domain of CHC22 interacts with SNX5 (and functionally redundant SNX6), which also binds the ERGIC tether p115; (2) an isoform-specific patch in the CHC22 N-terminal domain separately mediates direct binding to p115. Both interactions are independently required for CHC22 targeting to ERGIC membranes and for directing GLUT4 to the GSC; interference with either interaction inhibits GLUT4 targeting.\",\n      \"method\": \"Co-immunoprecipitation, domain mutagenesis/deletion mapping, siRNA knockdown of SNX5/SNX6, GLUT4 trafficking assays, immunofluorescence localization\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP with domain mutagenesis, epistatic knockdowns, functional GLUT4 trafficking readout, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"39160272\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CHC22 (CLTCL1) is a human-enriched clathrin heavy-chain isoform that forms triskelion-based vesicle coats with distinct biochemical properties from ubiquitous CHC17 (more pH-stable, resistant to Hsc70/auxilin uncoating, differently regulated by adaptors); it is recruited to ERGIC membranes via a bipartite mechanism requiring both its C-terminal trimerization domain binding SNX5/SNX6 (which also contacts ERGIC tether p115) and an isoform-specific N-terminal patch that directly binds p115, enabling CHC22 to mediate a Golgi-bypass route that sequesters GLUT4 into an intracellular storage compartment from which insulin can mobilize it to the plasma membrane, with a secondary role in retrograde endosome-to-TGN sorting (requiring syntaxin 10) that recaptures GLUT4 after endocytosis, and additional functions during skeletal muscle development, regeneration, and at neuromuscular junctions.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CLTCL1 encodes CHC22, a human-enriched clathrin heavy-chain isoform that builds triskelion-based vesicle coats biochemically distinct from the ubiquitous CHC17: the CHC22 coat is more pH-stable, is not disassembled by the Hsc70/auxilin uncoating machinery, is differentially recruited by adaptors, and does not support plasma-membrane endocytosis [#8]. Its central cellular role is the biogenesis of the insulin-responsive GLUT4 storage compartment in human skeletal muscle and adipocytes, a species-restricted function: depletion impairs GLUT4 sequestration, and ectopic expression in mice (which lack the gene) mislocalizes GLUT4 pathway components and produces diabetic features [#5]. CHC22 acts at the ER-to-Golgi intermediate compartment (ERGIC), where it forms a complex with the tether p115, GLUT4, and sortilin to route GLUT4 into the storage compartment, upstream of a separate retrograde endosome-to-TGN recapture step that requires syntaxin 10 [#6, #10]. Recruitment to ERGIC membranes is bipartite, requiring both the C-terminal trimerization domain binding SNX5/SNX6 (which itself contacts p115) and an isoform-specific N-terminal patch that binds p115 directly; disruption of either interaction blocks GLUT4 targeting [#11, #4]. A common coding variant (V1316) alters CHC22 dynamics and is less effective at controlling GLUT4 traffic, and CLTCL1 is under strong purifying selection in vertebrates retaining it [#9]. CHC22 is enriched at neuromuscular and myotendinous junctions and is upregulated during myoblast differentiation and muscle regeneration, where it influences fiber-type metabolism [#4, #7]. A balanced translocation truncating CLTCL1 produces features of DiGeorge/velocardiofacial syndrome, implicating haploinsufficiency in that phenotype [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Establishing that humans possess a second clathrin heavy-chain gene distinct from the canonical CHC17 raised the question of whether a paralog with a specialized function exists.\",\n      \"evidence\": \"cDNA cloning, sequencing, and Northern analysis of a 1640-aa heavy chain on chromosome 22q11 with 84.7% identity to CHC17 and skeletal-muscle-selective expression\",\n      \"pmids\": [\n        \"8733129\",\n        \"8844170\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"no functional distinction from CHC17 established at this stage\",\n        \"biochemical consequence of the C-terminal alternative splicing untested\",\n        \"binding partners unknown\"\n      ]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Linking CLTCL1 disruption to a developmental syndrome tested whether the gene has a dosage-sensitive role in vivo.\",\n      \"evidence\": \"Breakpoint cloning of a balanced (21;22) translocation truncating CLTCL1 and Northern detection of the truncated transcript in a patient with DiGeorge/velocardiofacial features\",\n      \"pmids\": [\n        \"9147638\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"single case, causality vs contiguous-gene effects not resolved\",\n        \"molecular mechanism connecting truncation to phenotype unknown\"\n      ]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"An ALK fusion to CLTCL1 in anaplastic lymphoma showed that the CHC22 portion confers membrane targeting, indirectly demonstrating its vesicle-associated localization.\",\n      \"evidence\": \"cDNA cloning of a CLTCL-ALK fusion, immunostaining localizing the fusion to clathrin-coated vesicles, and in vitro kinase autophosphorylation assay\",\n      \"pmids\": [\n        \"10807789\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"informs only the targeting/oligomerization region, not endogenous CHC22 function\",\n        \"no normal-cell trafficking readout\"\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identifying SNX5 as a CHC22-specific partner via a domain absent in CHC17 provided the first molecular basis for divergent CHC22 function.\",\n      \"evidence\": \"Co-immunoprecipitation, domain mapping, fractionation, and immunofluorescence showing a coiled-coil CHC22–SNX5 interaction and junctional/regeneration-linked muscle expression\",\n      \"pmids\": [\n        \"15133132\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"downstream trafficking pathway not yet defined\",\n        \"cargo not identified at this stage\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrating that CHC22 is required to build insulin-responsive GLUT4 storage compartments defined its principal physiological cargo and a species-restricted metabolic role.\",\n      \"evidence\": \"CHC22 knockdown in human cells, CHC22 transgenic mice with GLUT4 mislocalization and diabetic features, and glucose tolerance testing\",\n      \"pmids\": [\n        \"19478182\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"step in the GLUT4 itinerary controlled by CHC22 not yet localized\",\n        \"direct molecular interactions with GLUT4 machinery undefined\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Placing CHC22 in a retrograde endosome-to-TGN route distinct from CHC17 and retromer identified a specific trafficking step underlying GLUT4 targeting.\",\n      \"evidence\": \"siRNA knockdown of CHC22 and syntaxin 10, cargo trafficking assays, and fractionation showing independent CHC22/CHC17 function\",\n      \"pmids\": [\n        \"20065094\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"whether retrograde sorting was the primary or a recapture step unresolved at the time\",\n        \"coat assembly properties not yet characterized\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Reconstituting CHC22 coats biochemically distinguished it from CHC17, explaining how a near-identical heavy chain forms a functionally separate coat.\",\n      \"evidence\": \"In vitro coat assembly/disassembly, EM of vesicles, endocytosis assays, and adaptor recruitment assays showing pH stability, Hsc70/auxilin resistance, and absence of plasma-membrane endocytosis\",\n      \"pmids\": [\n        \"29097553\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"physiological adaptors and membrane recruitment site not defined\",\n        \"structural basis for uncoating resistance not solved\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"A common coding allotype affecting GLUT4 control linked CHC22 sequence variation to metabolic physiology and revealed evolutionary constraint.\",\n      \"evidence\": \"Population genetics/phylogenetics with functional cellular GLUT4 trafficking assays and live-cell imaging comparing V1316 and M1316 allotypes\",\n      \"pmids\": [\n        \"31159924\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"mechanistic basis for allotype dynamic differences unresolved\",\n        \"organismal/clinical metabolic consequences in humans not established\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Localizing CHC22 to the ERGIC and identifying a p115–GLUT4–sortilin complex placed CHC22 at an upstream Golgi-bypass step in GSC biogenesis.\",\n      \"evidence\": \"siRNA knockdown, co-IP, RUSH secretory tracing, immunofluorescence, and a Legionella replication-vacuole assay requiring ERGIC membrane\",\n      \"pmids\": [\n        \"31863584\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"molecular mechanism of CHC22 recruitment to ERGIC not yet defined\",\n        \"role of sortilin in the complex not functionally required\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defining a bipartite two-site recruitment mechanism resolved how CHC22 is targeted to ERGIC membranes to direct GLUT4.\",\n      \"evidence\": \"Co-IP, domain mutagenesis/deletion mapping, SNX5/SNX6 knockdown, and GLUT4 trafficking assays showing both a C-terminal trimerization–SNX5/6 contact and an N-terminal isoform-specific patch binding p115 are independently required\",\n      \"pmids\": [\n        \"39160272\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"structural details of the N-terminal p115 patch not solved\",\n        \"regulation of recruitment by insulin signaling not addressed\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CHC22 coat formation, ERGIC recruitment, and insulin signaling are coordinated to release GLUT4 to the plasma membrane remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"no structure of CHC22 coat or its recruitment interfaces\",\n        \"mechanism coupling insulin signaling to GSC mobilization undefined\",\n        \"basis for resistance to Hsc70/auxilin uncoating unexplained\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0005198\",\n        \"supporting_discovery_ids\": [\n          8\n        ]\n      },\n      {\n        \"term_id\": \"GO:0060090\",\n        \"supporting_discovery_ids\": [\n          10,\n          11\n        ]\n      }\n    ],\n    \"localization\": [\n      {\n        \"term_id\": \"GO:0031410\",\n        \"supporting_discovery_ids\": [\n          3,\n          8\n        ]\n      },\n      {\n        \"term_id\": \"GO:0005783\",\n        \"supporting_discovery_ids\": [\n          10,\n          11\n        ]\n      },\n      {\n        \"term_id\": \"GO:0005794\",\n        \"supporting_discovery_ids\": [\n          6,\n          10\n        ]\n      },\n      {\n        \"term_id\": \"GO:0005768\",\n        \"supporting_discovery_ids\": [\n          6\n        ]\n      }\n    ],\n    \"pathway\": [\n      {\n        \"term_id\": \"R-HSA-5653656\",\n        \"supporting_discovery_ids\": [\n          6,\n          8,\n          10\n        ]\n      },\n      {\n        \"term_id\": \"R-HSA-382551\",\n        \"supporting_discovery_ids\": [\n          5,\n          10\n        ]\n      },\n      {\n        \"term_id\": \"R-HSA-9609507\",\n        \"supporting_discovery_ids\": [\n          10,\n          11\n        ]\n      }\n    ],\n    \"complexes\": [\n      \"CHC22 clathrin coat\",\n      \"CHC22-p115-GLUT4-sortilin ERGIC complex\"\n    ],\n    \"partners\": [\n      \"SNX5\",\n      \"SNX6\",\n      \"USO1/p115\",\n      \"GLUT4\",\n      \"SORT1\",\n      \"STX10\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}