{"gene":"TRIM63","run_date":"2026-04-28T21:43:00","timeline":{"discoveries":[{"year":2005,"finding":"TRIM63 (MuRF-1) physically interacts with a specific subset of myofibrillar proteins including titin, nebulin, NRAP, troponin-I (TnI), troponin-T (TnT), myosin light chain 2 (MLC-2), myotilin, and T-cap, as identified by yeast two-hybrid screens of skeletal muscle cDNA libraries. Western blot studies in MURF-1-deficient mice showed reduced ubiquitination of MLC-2 and TnI, consistent with TRIM63 functioning as an E3 ubiquitin ligase targeting these myofibrillar substrates. TRIM63 also interacts with 11 enzymes involved in ATP/energy production including mitochondrial ATP synthase and creatine kinase.","method":"Yeast two-hybrid screen, Western blot on MURF-1 KO mice, SPOTS blot peptide mapping","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (Y2H, KO mouse western blot, peptide mapping); moderate evidence from single lab","pmids":["15967462"],"is_preprint":false},{"year":2007,"finding":"TRIM63 (MuRF-1) is recruited to M-line titin via its C-terminal helical domain, which binds with high affinity to a surface groove spanning the A168-A170 Ig/FnIII module region of titin. Crystal structure of titin A168-A170 revealed an extended rigid architecture with a shallow surface groove and a loop protrusion that is a key mediator of MuRF-1 recognition. This interaction is thought to regulate myofibril turnover.","method":"Crystal structure determination, isothermal calorimetry, SPOTS blot, pull-down assays, circular dichroism, SEC-MALS","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 1 — crystal structure combined with biophysical binding assays and mutagenesis-equivalent pull-down validation","pmids":["17215480"],"is_preprint":false},{"year":2013,"finding":"TRIM63 regulates fasting-induced turnover of nicotinic acetylcholine receptors (CHRN) at the neuromuscular junction via selective autophagy. TRIM63 co-localizes with endo/lysosomal vesicles containing CHRN, the membrane remodeler SH3GLB1, and the selective autophagy receptor SQSTM1. In trim63(-/-) mice, denervation-induced upregulation of SQSTM1 and LC3-II was abolished, and SQSTM1 did not colocalize with CHRN vesicles. Denervation-induced increase in autophagic CHRN vesicles was completely blunted in the absence of TRIM63.","method":"Trim63 knockout mouse model, immunofluorescence colocalization, Western blot, ATG7 knockout comparison, co-precipitation","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 — clean KO mouse with defined cellular phenotype and multiple orthogonal methods across two KO models","pmids":["24220501"],"is_preprint":false},{"year":2014,"finding":"SMAD3 augments FoxO3-induced MuRF-1 (TRIM63) promoter activity in a DNA-binding-dependent manner. FoxO3 and SMAD3 coexpression synergistically increased MuRF-1 mRNA and promoter activity in cultured myotubes. Mutation of the SMAD-binding element (SBE) in the proximal MuRF-1 promoter or use of a SMAD3 DNA-binding mutant attenuated FoxO3-dependent MuRF-1 promoter activation. Chromatin immunoprecipitation showed SMAD3 DNA binding increased FoxO3 abundance at the MuRF-1 promoter.","method":"Promoter reporter assay, ChIP, site-directed mutagenesis of SBE, overexpression in myotubes and HEK293 cells","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 1-2 — promoter mutagenesis, ChIP, and reporter assays with multiple orthogonal methods in single study","pmids":["24920680"],"is_preprint":false},{"year":2001,"finding":"A novel striated muscle RING zinc finger protein (SMRZ, later identified as TRIM63/MuRF-1) interacts with SMT3b (SUMO-2) via its N-terminal RING domain. Mutagenesis of conserved RING domain residues abolished this interaction. Transient transfection into C2C12 myoblasts showed nuclear localization of SMRZ. The gene is expressed exclusively in striated muscle and is developmentally regulated (higher in fetal than adult heart).","method":"Yeast two-hybrid, RING domain mutagenesis, Northern blot, FISH, transient transfection with subcellular localization","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — RING domain mutagenesis with interaction assay, but single lab and early characterization study","pmids":["11283016"],"is_preprint":false},{"year":2020,"finding":"TRIM63 (MuRF-1) functions as a RING-finger E3 ubiquitin ligase in striated muscle with dual roles: it promotes skeletal muscle atrophy by ubiquitinating myofibrillar substrates for proteasomal degradation, while playing a cardioprotective role in the heart. Its substrates include titin, troponin I, myosin heavy chain, and other sarcomeric proteins. TRIM63 localization includes the sarcomere M-line (via titin binding), the cytoplasm, and the nucleus.","method":"Review synthesizing in vitro ubiquitination assays, KO mouse studies, and biochemical fractionation/localization experiments from multiple studies","journal":"International journal of molecular sciences","confidence":"High","confidence_rationale":"Tier 2 — Strong; synthesis of replicated findings across multiple independent labs with in vitro ubiquitination assays and KO models","pmids":["32933049"],"is_preprint":false},{"year":2020,"finding":"Biallelic (homozygous or compound heterozygous) loss-of-function variants in TRIM63 cause an autosomal-recessive form of hypertrophic cardiomyopathy (HCM) with concentric left ventricular hypertrophy. Heterozygous carriers were unaffected, establishing recessive inheritance. Clinical features included high rates of late gadolinium enhancement and ventricular tachycardia.","method":"Next-generation sequencing of 4867 HCM index cases, familial segregation analysis","journal":"Heart (British Cardiac Society)","confidence":"Medium","confidence_rationale":"Tier 2 — large cohort genetic study with familial segregation establishing loss-of-function mechanism, but no in vitro mechanistic follow-up","pmids":["32451364"],"is_preprint":false},{"year":2021,"finding":"TRIM63 mRNA is highly and specifically expressed in MiT family aberration-associated renal cell carcinoma (MiTF-RCC) harboring TFE3 or TFEB gene rearrangements, compared to other RCC subtypes. RNA-ISH confirmed this expression pattern in 177 RCC cases, including TFE3 FISH false-negative cases with RBM10-TFE3 inversions. This establishes TRIM63 as a transcriptional target downstream of TFE3/TFEB fusion oncoproteins.","method":"RNAseq, RNA in situ hybridization (RNA-ISH), FISH validation in 177 clinical cases","journal":"Modern pathology","confidence":"Medium","confidence_rationale":"Tier 3 — expression-based finding with clinical validation but limited molecular mechanism of TFE3-driven TRIM63 regulation","pmids":["33854184"],"is_preprint":false}],"current_model":"TRIM63 (MuRF-1) is a striated muscle-specific RING-finger E3 ubiquitin ligase that localizes to the sarcomere M-line via its C-terminal helical domain binding to titin (A168-A170 modules), ubiquitinates myofibrillar substrates including troponin-I, myosin light chain 2, and titin to promote proteasomal degradation during skeletal muscle atrophy, and also regulates nicotinic acetylcholine receptor turnover at the neuromuscular junction through selective autophagy involving SQSTM1 and SH3GLB1; its transcription is co-regulated by FoxO3 and SMAD3 via a conserved FRE-SBE motif in the proximal promoter, and biallelic loss-of-function causes autosomal-recessive hypertrophic cardiomyopathy."},"narrative":{"teleology":[{"year":2001,"claim":"Initial identification of TRIM63 as a striated-muscle-restricted RING finger protein that interacts with SUMO-2 via its RING domain established this gene as a potential signaling node in muscle, though its enzymatic activity was not yet defined.","evidence":"Yeast two-hybrid and RING domain mutagenesis in C2C12 myoblasts","pmids":["11283016"],"confidence":"Medium","gaps":["SUMO-2 interaction not confirmed by reciprocal pull-down or in vivo assay","E3 ligase activity not yet demonstrated","Nuclear localization seen only in transiently transfected myoblasts, not endogenous protein"]},{"year":2005,"claim":"Systematic mapping of TRIM63 substrates revealed it interacts with and ubiquitinates key myofibrillar proteins (troponin-I, MLC-2) and metabolic enzymes, establishing it as an E3 ligase that targets both structural and metabolic components of the sarcomere.","evidence":"Yeast two-hybrid screen of skeletal muscle cDNA library combined with Western blot analysis of MuRF-1 knockout mice showing reduced substrate ubiquitination","pmids":["15967462"],"confidence":"High","gaps":["In vitro reconstituted ubiquitination assays for each individual substrate not performed in this study","Relative contribution of each substrate to atrophy phenotype unknown"]},{"year":2007,"claim":"Crystal structure of the titin A168-A170 region and biophysical binding studies revealed how TRIM63 is physically recruited to the sarcomere M-line via a shallow surface groove on titin, providing a structural basis for localized substrate ubiquitination.","evidence":"X-ray crystallography, isothermal calorimetry, and pull-down assays","pmids":["17215480"],"confidence":"High","gaps":["No structure of the TRIM63 C-terminal helical domain itself or the full complex","Whether titin binding is required for substrate ubiquitination in vivo not tested"]},{"year":2013,"claim":"Discovery that TRIM63 drives selective autophagy of nicotinic acetylcholine receptors at the neuromuscular junction via SQSTM1 and SH3GLB1 expanded its role beyond proteasomal degradation to include autophagic membrane receptor turnover.","evidence":"Trim63 knockout mice with denervation, immunofluorescence colocalization, and comparison with ATG7 knockout","pmids":["24220501"],"confidence":"High","gaps":["Whether TRIM63 directly ubiquitinates CHRN subunits or acts indirectly through SQSTM1 not resolved","Mechanism linking TRIM63 RING activity to autophagosome formation not defined"]},{"year":2014,"claim":"Identification of synergistic FoxO3-SMAD3 co-regulation of TRIM63 transcription through a conserved FRE-SBE promoter element explained how TGF-β and insulin/Akt pathways converge to control atrophy gene expression.","evidence":"ChIP, promoter-reporter mutagenesis, and SMAD3 DNA-binding mutant analysis in cultured myotubes","pmids":["24920680"],"confidence":"High","gaps":["In vivo validation of SBE requirement for TRIM63 induction during atrophy not performed","Other transcription factors contributing to TRIM63 regulation not systematically explored"]},{"year":2020,"claim":"Large-cohort human genetic studies established that biallelic TRIM63 loss-of-function causes autosomal-recessive hypertrophic cardiomyopathy, revealing a non-redundant cardioprotective role distinct from its skeletal muscle atrophy function.","evidence":"Next-generation sequencing of 4867 HCM index cases with familial segregation analysis","pmids":["32451364"],"confidence":"Medium","gaps":["No functional rescue or in vitro mechanistic follow-up of identified variants","Cardiac-specific substrates whose accumulation drives HCM not identified","Relationship between heterozygous carrier status and subclinical phenotypes not explored"]},{"year":null,"claim":"The mechanism by which TRIM63 loss leads to hypertrophic cardiomyopathy—specifically which cardiac substrates accumulate and whether proteasomal or autophagic pathways are impaired—remains undefined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No cardiac-specific substrate identification for TRIM63","No structural model of full-length TRIM63 or TRIM63-substrate complexes","Whether TRIM63 autophagic and proteasomal functions are independently regulated is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,5]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,5]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[5]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,5]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,5]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[2]},{"term_id":"R-HSA-397014","term_label":"Muscle contraction","supporting_discovery_ids":[0,1,5]}],"complexes":[],"partners":["TTN","TNNI1","MYL2","SQSTM1","SH3GLB1","SMAD3","FOXO3"],"other_free_text":[]},"mechanistic_narrative":"TRIM63 (MuRF-1) is a striated muscle-specific RING-finger E3 ubiquitin ligase that anchors to the sarcomere M-line through high-affinity binding of its C-terminal helical domain to titin A168-A170 modules, where it ubiquitinates myofibrillar substrates—including troponin-I, myosin light chain 2, and titin—to drive proteasomal degradation during skeletal muscle atrophy [PMID:15967462, PMID:17215480, PMID:32933049]. Beyond proteasomal targeting, TRIM63 promotes selective autophagy of nicotinic acetylcholine receptors at the neuromuscular junction through a pathway involving SQSTM1 and SH3GLB1, and its transcription is synergistically activated by FoxO3 and SMAD3 via a conserved FRE-SBE motif in the proximal promoter [PMID:24220501, PMID:24920680]. Biallelic loss-of-function variants in TRIM63 cause autosomal-recessive hypertrophic cardiomyopathy with concentric left ventricular hypertrophy [PMID:32451364]."},"prefetch_data":{"uniprot":{"accession":"Q969Q1","full_name":"E3 ubiquitin-protein ligase TRIM63","aliases":["Iris RING finger protein","Muscle-specific RING finger protein 1","MuRF-1","MuRF1","RING finger protein 28","RING-type E3 ubiquitin transferase TRIM63","Striated muscle RING zinc finger protein","Tripartite motif-containing protein 63"],"length_aa":353,"mass_kda":40.2,"function":"E3 ubiquitin ligase. Mediates the ubiquitination and subsequent proteasomal degradation of CKM, GMEB1 and HIBADH. Regulates the proteasomal degradation of muscle proteins under amino acid starvation, where muscle protein is catabolized to provide other organs with amino acids. Inhibits de novo skeletal muscle protein synthesis under amino acid starvation. Regulates proteasomal degradation of cardiac troponin I/TNNI3 and probably of other sarcomeric-associated proteins. May play a role in striated muscle atrophy and hypertrophy by regulating an anti-hypertrophic PKC-mediated signaling pathway. May regulate the organization of myofibrils through TTN in muscle cells","subcellular_location":"Cytoplasm; Nucleus; Cytoplasm, myofibril, sarcomere, M line; Cytoplasm, myofibril, sarcomere, Z line","url":"https://www.uniprot.org/uniprotkb/Q969Q1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TRIM63","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TRIM63","total_profiled":1310},"omim":[{"mim_id":"621270","title":"CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 31; CMH31","url":"https://www.omim.org/entry/621270"},{"mim_id":"620942","title":"SYNPO2 INTRON SENSE-OVERLAPPING LONG NONCODING RNA","url":"https://www.omim.org/entry/620942"},{"mim_id":"616755","title":"TRIPARTITE MOTIF-CONTAINING PROTEIN 62; TRIM62","url":"https://www.omim.org/entry/616755"},{"mim_id":"607212","title":"CASPASE RECRUITMENT DOMAIN-CONTAINING PROTEIN 9; CARD9","url":"https://www.omim.org/entry/607212"},{"mim_id":"606831","title":"NLR FAMILY, CASPASE RECRUITMENT DOMAIN-CONTAINING 4; NLRC4","url":"https://www.omim.org/entry/606831"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"skeletal muscle","ntpm":1847.0}],"url":"https://www.proteinatlas.org/search/TRIM63"},"hgnc":{"alias_symbol":["MURF-1","IRF","SMRZ"],"prev_symbol":["RNF28"]},"alphafold":{"accession":"Q969Q1","domains":[{"cath_id":"3.30.40.10","chopping":"14-59_70-112","consensus_level":"high","plddt":87.8049,"start":14,"end":112},{"cath_id":"-","chopping":"173-300","consensus_level":"medium","plddt":92.2623,"start":173,"end":300}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q969Q1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q969Q1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q969Q1-F1-predicted_aligned_error_v6.png","plddt_mean":82.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TRIM63","jax_strain_url":"https://www.jax.org/strain/search?query=TRIM63"},"sequence":{"accession":"Q969Q1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q969Q1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q969Q1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q969Q1"}},"corpus_meta":[{"pmid":"16125763","id":"PMC_16125763","title":"Identification 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differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/18688264","citation_count":61,"is_preprint":false},{"pmid":"19351818","id":"PMC_19351818","title":"IRF-9/STAT2 [corrected] functional interaction drives retinoic acid-induced gene G expression independently of STAT1.","date":"2009","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/19351818","citation_count":59,"is_preprint":false},{"pmid":"23938252","id":"PMC_23938252","title":"Phytoestrogens mediated anti-inflammatory effect through suppression of IRF-1 and pSTAT1 expressions in lipopolysaccharide-activated microglia.","date":"2013","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/23938252","citation_count":58,"is_preprint":false},{"pmid":"23840248","id":"PMC_23840248","title":"AP-1/IRF-3 Targeted Anti-Inflammatory Activity of Andrographolide Isolated from Andrographis paniculata.","date":"2013","source":"Evidence-based complementary and alternative medicine : eCAM","url":"https://pubmed.ncbi.nlm.nih.gov/23840248","citation_count":55,"is_preprint":false},{"pmid":"16754320","id":"PMC_16754320","title":"Toll-like receptor signaling and IRF transcription factors.","date":"2006","source":"IUBMB life","url":"https://pubmed.ncbi.nlm.nih.gov/16754320","citation_count":54,"is_preprint":false},{"pmid":"15511228","id":"PMC_15511228","title":"IFN-gamma enhances TRAIL-induced apoptosis through IRF-1.","date":"2004","source":"European journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15511228","citation_count":53,"is_preprint":false},{"pmid":"24920680","id":"PMC_24920680","title":"SMAD3 augments FoxO3-induced MuRF-1 promoter activity in a DNA-binding-dependent manner.","date":"2014","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/24920680","citation_count":50,"is_preprint":false},{"pmid":"16966383","id":"PMC_16966383","title":"IRF-1 deficiency skews the differentiation of dendritic cells toward plasmacytoid and tolerogenic features.","date":"2006","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/16966383","citation_count":48,"is_preprint":false},{"pmid":"12592391","id":"PMC_12592391","title":"IRF-1 reverts the transformed phenotype of oncogenically transformed cells in vitro and in vivo.","date":"2003","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/12592391","citation_count":48,"is_preprint":false},{"pmid":"1614874","id":"PMC_1614874","title":"Distinct activation of murine interferon-alpha promoter region by IRF-1/ISFG-2 and virus infection.","date":"1992","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/1614874","citation_count":48,"is_preprint":false},{"pmid":"22535200","id":"PMC_22535200","title":"Unique contribution of IRF-5-Ikaros axis to the B-cell IgG2a response.","date":"2012","source":"Genes and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/22535200","citation_count":46,"is_preprint":false},{"pmid":"19606498","id":"PMC_19606498","title":"STAT1/IRF-1 signaling pathway mediates the injurious effect of interferon-gamma on oligodendrocyte progenitor cells.","date":"2010","source":"Glia","url":"https://pubmed.ncbi.nlm.nih.gov/19606498","citation_count":45,"is_preprint":false},{"pmid":"33854184","id":"PMC_33854184","title":"TRIM63 is a sensitive and specific biomarker for MiT family aberration-associated renal cell carcinoma.","date":"2021","source":"Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc","url":"https://pubmed.ncbi.nlm.nih.gov/33854184","citation_count":44,"is_preprint":false},{"pmid":"35235107","id":"PMC_35235107","title":"Lipoxin A4 regulates M1/M2 macrophage polarization via FPR2-IRF pathway.","date":"2022","source":"Inflammopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/35235107","citation_count":44,"is_preprint":false},{"pmid":"29751576","id":"PMC_29751576","title":"Thymoquinone Suppresses IRF-3-Mediated Expression of Type I Interferons via Suppression of TBK1.","date":"2018","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/29751576","citation_count":43,"is_preprint":false},{"pmid":"11846973","id":"PMC_11846973","title":"IRF regulation of HIV-1 long terminal repeat activity.","date":"2002","source":"Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research","url":"https://pubmed.ncbi.nlm.nih.gov/11846973","citation_count":42,"is_preprint":false},{"pmid":"18778729","id":"PMC_18778729","title":"Structural and functional studies of an IRF-7-like gene from Atlantic salmon.","date":"2009","source":"Developmental and comparative immunology","url":"https://pubmed.ncbi.nlm.nih.gov/18778729","citation_count":41,"is_preprint":false},{"pmid":"18713947","id":"PMC_18713947","title":"IRF-4 functions as a tumor suppressor in early B-cell development.","date":"2008","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/18713947","citation_count":41,"is_preprint":false},{"pmid":"29753657","id":"PMC_29753657","title":"IRF-1, RIG-I and MDA5 display potent antiviral activities against norovirus coordinately induced by different types of interferons.","date":"2018","source":"Antiviral research","url":"https://pubmed.ncbi.nlm.nih.gov/29753657","citation_count":40,"is_preprint":false},{"pmid":"29669755","id":"PMC_29669755","title":"Zinc finger-IRF composite elements bound by Ikaros/IRF4 complexes function as gene repression in plasma cell.","date":"2018","source":"Blood advances","url":"https://pubmed.ncbi.nlm.nih.gov/29669755","citation_count":40,"is_preprint":false},{"pmid":"11175354","id":"PMC_11175354","title":"A novel role for IRF-1 as a suppressor of apoptosis.","date":"2000","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/11175354","citation_count":38,"is_preprint":false},{"pmid":"25847975","id":"PMC_25847975","title":"CCL7 and IRF-7 Mediate Hallmark Inflammatory and IFN Responses following Rhinovirus 1B Infection.","date":"2015","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/25847975","citation_count":38,"is_preprint":false},{"pmid":"9204971","id":"PMC_9204971","title":"Expression of interferon regulatory factor (IRF) genes and response to interferon-alpha in chronic myeloid leukaemia.","date":"1997","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/9204971","citation_count":38,"is_preprint":false},{"pmid":"32451364","id":"PMC_32451364","title":"Mutations in TRIM63 cause an autosomal-recessive form of hypertrophic cardiomyopathy.","date":"2020","source":"Heart (British Cardiac Society)","url":"https://pubmed.ncbi.nlm.nih.gov/32451364","citation_count":37,"is_preprint":false},{"pmid":"11283016","id":"PMC_11283016","title":"A novel human striated muscle RING zinc finger protein, SMRZ, interacts with SMT3b via its RING domain.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11283016","citation_count":36,"is_preprint":false},{"pmid":"40246950","id":"PMC_40246950","title":"Ionizable lipid nanoparticles of mRNA vaccines elicit NF-κB and IRF responses through toll-like receptor 4.","date":"2025","source":"NPJ vaccines","url":"https://pubmed.ncbi.nlm.nih.gov/40246950","citation_count":36,"is_preprint":false},{"pmid":"16857162","id":"PMC_16857162","title":"Alternative splicing variants of IRF-1 lacking exons 7, 8, and 9 in cervical cancer.","date":"2006","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/16857162","citation_count":36,"is_preprint":false},{"pmid":"10064616","id":"PMC_10064616","title":"Psoriatic keratinocytes show reduced IRF-1 and STAT-1alpha activation in response to gamma-IFN.","date":"1999","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/10064616","citation_count":35,"is_preprint":false},{"pmid":"36384204","id":"PMC_36384204","title":"Non-canonical NF-κB contributes to endothelial pyroptosis and atherogenesis dependent on IRF-1.","date":"2022","source":"Translational research : the journal of laboratory and clinical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36384204","citation_count":34,"is_preprint":false},{"pmid":"25320290","id":"PMC_25320290","title":"Differentiation of neurons restricts Arbovirus replication and increases expression of the alpha isoform of IRF-7.","date":"2014","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/25320290","citation_count":34,"is_preprint":false},{"pmid":"19786094","id":"PMC_19786094","title":"IKKalpha negatively regulates IRF-5 function in a MyD88-TRAF6 pathway.","date":"2009","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/19786094","citation_count":33,"is_preprint":false},{"pmid":"21454650","id":"PMC_21454650","title":"Interferon regulatory factor 4 (IRF-4) targets IRF-5 to regulate Epstein-Barr virus transformation.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21454650","citation_count":32,"is_preprint":false},{"pmid":"27379868","id":"PMC_27379868","title":"Specificity and Function of IRF Family Transcription Factors: Insights from Genomics.","date":"2016","source":"Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research","url":"https://pubmed.ncbi.nlm.nih.gov/27379868","citation_count":31,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":44990,"output_tokens":2609,"usd":0.087053},"stage2":{"model":"claude-opus-4-6","input_tokens":5752,"output_tokens":2025,"usd":0.119078},"total_usd":0.206131,"stage1_batch_id":"msgbatch_01RPbVc9PDH9zQmYK5Hs6srm","stage2_batch_id":"msgbatch_01JVbVLzeKN2yVrsGp3zC8aM","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify papers about TRIM63 (also known as MuRF-1, Muscle RING Finger 1). The vast majority of papers in this corpus are about IRF (Interferon Regulatory Factor) transcription factors, which is a symbol collision. I need to focus only on the TRIM63/MuRF-1 papers.\n\nRelevant TRIM63 papers: 16, 20, 27, 42, 50, 51, 52, 74, 80, 91, 92\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"TRIM63 (MuRF-1) physically interacts with a specific subset of myofibrillar proteins including titin, nebulin, NRAP, troponin-I (TnI), troponin-T (TnT), myosin light chain 2 (MLC-2), myotilin, and T-cap, as identified by yeast two-hybrid screens of skeletal muscle cDNA libraries. Western blot studies in MURF-1-deficient mice showed reduced ubiquitination of MLC-2 and TnI, consistent with TRIM63 functioning as an E3 ubiquitin ligase targeting these myofibrillar substrates. TRIM63 also interacts with 11 enzymes involved in ATP/energy production including mitochondrial ATP synthase and creatine kinase.\",\n      \"method\": \"Yeast two-hybrid screen, Western blot on MURF-1 KO mice, SPOTS blot peptide mapping\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Y2H, KO mouse western blot, peptide mapping); moderate evidence from single lab\",\n      \"pmids\": [\"15967462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"TRIM63 (MuRF-1) is recruited to M-line titin via its C-terminal helical domain, which binds with high affinity to a surface groove spanning the A168-A170 Ig/FnIII module region of titin. Crystal structure of titin A168-A170 revealed an extended rigid architecture with a shallow surface groove and a loop protrusion that is a key mediator of MuRF-1 recognition. This interaction is thought to regulate myofibril turnover.\",\n      \"method\": \"Crystal structure determination, isothermal calorimetry, SPOTS blot, pull-down assays, circular dichroism, SEC-MALS\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure combined with biophysical binding assays and mutagenesis-equivalent pull-down validation\",\n      \"pmids\": [\"17215480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TRIM63 regulates fasting-induced turnover of nicotinic acetylcholine receptors (CHRN) at the neuromuscular junction via selective autophagy. TRIM63 co-localizes with endo/lysosomal vesicles containing CHRN, the membrane remodeler SH3GLB1, and the selective autophagy receptor SQSTM1. In trim63(-/-) mice, denervation-induced upregulation of SQSTM1 and LC3-II was abolished, and SQSTM1 did not colocalize with CHRN vesicles. Denervation-induced increase in autophagic CHRN vesicles was completely blunted in the absence of TRIM63.\",\n      \"method\": \"Trim63 knockout mouse model, immunofluorescence colocalization, Western blot, ATG7 knockout comparison, co-precipitation\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO mouse with defined cellular phenotype and multiple orthogonal methods across two KO models\",\n      \"pmids\": [\"24220501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SMAD3 augments FoxO3-induced MuRF-1 (TRIM63) promoter activity in a DNA-binding-dependent manner. FoxO3 and SMAD3 coexpression synergistically increased MuRF-1 mRNA and promoter activity in cultured myotubes. Mutation of the SMAD-binding element (SBE) in the proximal MuRF-1 promoter or use of a SMAD3 DNA-binding mutant attenuated FoxO3-dependent MuRF-1 promoter activation. Chromatin immunoprecipitation showed SMAD3 DNA binding increased FoxO3 abundance at the MuRF-1 promoter.\",\n      \"method\": \"Promoter reporter assay, ChIP, site-directed mutagenesis of SBE, overexpression in myotubes and HEK293 cells\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — promoter mutagenesis, ChIP, and reporter assays with multiple orthogonal methods in single study\",\n      \"pmids\": [\"24920680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"A novel striated muscle RING zinc finger protein (SMRZ, later identified as TRIM63/MuRF-1) interacts with SMT3b (SUMO-2) via its N-terminal RING domain. Mutagenesis of conserved RING domain residues abolished this interaction. Transient transfection into C2C12 myoblasts showed nuclear localization of SMRZ. The gene is expressed exclusively in striated muscle and is developmentally regulated (higher in fetal than adult heart).\",\n      \"method\": \"Yeast two-hybrid, RING domain mutagenesis, Northern blot, FISH, transient transfection with subcellular localization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RING domain mutagenesis with interaction assay, but single lab and early characterization study\",\n      \"pmids\": [\"11283016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRIM63 (MuRF-1) functions as a RING-finger E3 ubiquitin ligase in striated muscle with dual roles: it promotes skeletal muscle atrophy by ubiquitinating myofibrillar substrates for proteasomal degradation, while playing a cardioprotective role in the heart. Its substrates include titin, troponin I, myosin heavy chain, and other sarcomeric proteins. TRIM63 localization includes the sarcomere M-line (via titin binding), the cytoplasm, and the nucleus.\",\n      \"method\": \"Review synthesizing in vitro ubiquitination assays, KO mouse studies, and biochemical fractionation/localization experiments from multiple studies\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Strong; synthesis of replicated findings across multiple independent labs with in vitro ubiquitination assays and KO models\",\n      \"pmids\": [\"32933049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Biallelic (homozygous or compound heterozygous) loss-of-function variants in TRIM63 cause an autosomal-recessive form of hypertrophic cardiomyopathy (HCM) with concentric left ventricular hypertrophy. Heterozygous carriers were unaffected, establishing recessive inheritance. Clinical features included high rates of late gadolinium enhancement and ventricular tachycardia.\",\n      \"method\": \"Next-generation sequencing of 4867 HCM index cases, familial segregation analysis\",\n      \"journal\": \"Heart (British Cardiac Society)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — large cohort genetic study with familial segregation establishing loss-of-function mechanism, but no in vitro mechanistic follow-up\",\n      \"pmids\": [\"32451364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIM63 mRNA is highly and specifically expressed in MiT family aberration-associated renal cell carcinoma (MiTF-RCC) harboring TFE3 or TFEB gene rearrangements, compared to other RCC subtypes. RNA-ISH confirmed this expression pattern in 177 RCC cases, including TFE3 FISH false-negative cases with RBM10-TFE3 inversions. This establishes TRIM63 as a transcriptional target downstream of TFE3/TFEB fusion oncoproteins.\",\n      \"method\": \"RNAseq, RNA in situ hybridization (RNA-ISH), FISH validation in 177 clinical cases\",\n      \"journal\": \"Modern pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — expression-based finding with clinical validation but limited molecular mechanism of TFE3-driven TRIM63 regulation\",\n      \"pmids\": [\"33854184\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TRIM63 (MuRF-1) is a striated muscle-specific RING-finger E3 ubiquitin ligase that localizes to the sarcomere M-line via its C-terminal helical domain binding to titin (A168-A170 modules), ubiquitinates myofibrillar substrates including troponin-I, myosin light chain 2, and titin to promote proteasomal degradation during skeletal muscle atrophy, and also regulates nicotinic acetylcholine receptor turnover at the neuromuscular junction through selective autophagy involving SQSTM1 and SH3GLB1; its transcription is co-regulated by FoxO3 and SMAD3 via a conserved FRE-SBE motif in the proximal promoter, and biallelic loss-of-function causes autosomal-recessive hypertrophic cardiomyopathy.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TRIM63 (MuRF-1) is a striated muscle-specific RING-finger E3 ubiquitin ligase that anchors to the sarcomere M-line through high-affinity binding of its C-terminal helical domain to titin A168-A170 modules, where it ubiquitinates myofibrillar substrates—including troponin-I, myosin light chain 2, and titin—to drive proteasomal degradation during skeletal muscle atrophy [PMID:15967462, PMID:17215480, PMID:32933049]. Beyond proteasomal targeting, TRIM63 promotes selective autophagy of nicotinic acetylcholine receptors at the neuromuscular junction through a pathway involving SQSTM1 and SH3GLB1, and its transcription is synergistically activated by FoxO3 and SMAD3 via a conserved FRE-SBE motif in the proximal promoter [PMID:24220501, PMID:24920680]. Biallelic loss-of-function variants in TRIM63 cause autosomal-recessive hypertrophic cardiomyopathy with concentric left ventricular hypertrophy [PMID:32451364].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Initial identification of TRIM63 as a striated-muscle-restricted RING finger protein that interacts with SUMO-2 via its RING domain established this gene as a potential signaling node in muscle, though its enzymatic activity was not yet defined.\",\n      \"evidence\": \"Yeast two-hybrid and RING domain mutagenesis in C2C12 myoblasts\",\n      \"pmids\": [\"11283016\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"SUMO-2 interaction not confirmed by reciprocal pull-down or in vivo assay\",\n        \"E3 ligase activity not yet demonstrated\",\n        \"Nuclear localization seen only in transiently transfected myoblasts, not endogenous protein\"\n      ]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Systematic mapping of TRIM63 substrates revealed it interacts with and ubiquitinates key myofibrillar proteins (troponin-I, MLC-2) and metabolic enzymes, establishing it as an E3 ligase that targets both structural and metabolic components of the sarcomere.\",\n      \"evidence\": \"Yeast two-hybrid screen of skeletal muscle cDNA library combined with Western blot analysis of MuRF-1 knockout mice showing reduced substrate ubiquitination\",\n      \"pmids\": [\"15967462\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"In vitro reconstituted ubiquitination assays for each individual substrate not performed in this study\",\n        \"Relative contribution of each substrate to atrophy phenotype unknown\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Crystal structure of the titin A168-A170 region and biophysical binding studies revealed how TRIM63 is physically recruited to the sarcomere M-line via a shallow surface groove on titin, providing a structural basis for localized substrate ubiquitination.\",\n      \"evidence\": \"X-ray crystallography, isothermal calorimetry, and pull-down assays\",\n      \"pmids\": [\"17215480\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structure of the TRIM63 C-terminal helical domain itself or the full complex\",\n        \"Whether titin binding is required for substrate ubiquitination in vivo not tested\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Discovery that TRIM63 drives selective autophagy of nicotinic acetylcholine receptors at the neuromuscular junction via SQSTM1 and SH3GLB1 expanded its role beyond proteasomal degradation to include autophagic membrane receptor turnover.\",\n      \"evidence\": \"Trim63 knockout mice with denervation, immunofluorescence colocalization, and comparison with ATG7 knockout\",\n      \"pmids\": [\"24220501\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether TRIM63 directly ubiquitinates CHRN subunits or acts indirectly through SQSTM1 not resolved\",\n        \"Mechanism linking TRIM63 RING activity to autophagosome formation not defined\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identification of synergistic FoxO3-SMAD3 co-regulation of TRIM63 transcription through a conserved FRE-SBE promoter element explained how TGF-β and insulin/Akt pathways converge to control atrophy gene expression.\",\n      \"evidence\": \"ChIP, promoter-reporter mutagenesis, and SMAD3 DNA-binding mutant analysis in cultured myotubes\",\n      \"pmids\": [\"24920680\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"In vivo validation of SBE requirement for TRIM63 induction during atrophy not performed\",\n        \"Other transcription factors contributing to TRIM63 regulation not systematically explored\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Large-cohort human genetic studies established that biallelic TRIM63 loss-of-function causes autosomal-recessive hypertrophic cardiomyopathy, revealing a non-redundant cardioprotective role distinct from its skeletal muscle atrophy function.\",\n      \"evidence\": \"Next-generation sequencing of 4867 HCM index cases with familial segregation analysis\",\n      \"pmids\": [\"32451364\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No functional rescue or in vitro mechanistic follow-up of identified variants\",\n        \"Cardiac-specific substrates whose accumulation drives HCM not identified\",\n        \"Relationship between heterozygous carrier status and subclinical phenotypes not explored\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The mechanism by which TRIM63 loss leads to hypertrophic cardiomyopathy—specifically which cardiac substrates accumulate and whether proteasomal or autophagic pathways are impaired—remains undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No cardiac-specific substrate identification for TRIM63\",\n        \"No structural model of full-length TRIM63 or TRIM63-substrate complexes\",\n        \"Whether TRIM63 autophagic and proteasomal functions are independently regulated is unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 5]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [0, 1, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"TTN\",\n      \"TNNI1\",\n      \"MYL2\",\n      \"SQSTM1\",\n      \"SH3GLB1\",\n      \"SMAD3\",\n      \"FOXO3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}