{"gene":"TRIM41","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2007,"finding":"TRIM41/RINCK was identified as an E3 ubiquitin ligase that interacts with protein kinase C (PKC) via the C1A domain of PKC (identified by yeast two-hybrid with PKCβ N-terminus as bait). TRIM41 ubiquitinates PKC both in vitro and in cells, leading to PKC degradation and reduced PKC levels; this mechanism is independent of phorbol ester-mediated PKC downregulation and applies to conventional, novel, and atypical PKC isozymes.","method":"Yeast two-hybrid screen, co-immunoprecipitation, in vitro and cellular ubiquitination assay, overexpression and siRNA knockdown with PKC level readout","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro ubiquitination assay plus cellular co-IP and genetic knockdown/overexpression with multiple orthogonal methods in one study","pmids":["17893151"],"is_preprint":false},{"year":2005,"finding":"TRIM41 protein (isoforms alpha and beta) localizes as speckles in both cytoplasm and nucleus of cells. Nuclear transport is mediated by an N-terminal segment common to both isoforms but is independent of a classical nuclear localization signal sequence, as determined by GFP fusion constructs and subcellular fractionation.","method":"GFP fusion live-cell imaging of truncation mutants, Western blot of cellular fractions","journal":"Molecular biology reports","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — direct localization by GFP fusions with domain mapping and fractionation validation, single lab","pmids":["16022281"],"is_preprint":false},{"year":2018,"finding":"TRIM41 interacts with influenza A virus nucleoprotein (NP) through its SPRY domain, ubiquitinates NP in vitro and in cells, and promotes NP polyubiquitination and proteasomal degradation, thereby restricting IAV infection. A TRIM41 RING-domain mutant lacking E3 ligase activity failed to inhibit IAV infection, demonstrating that E3 ligase activity is essential for antiviral function.","method":"Co-immunoprecipitation, in vitro ubiquitination assay, RNAi knockdown and CRISPR knockout of TRIM41, TRIM41 overexpression, E3 ligase-dead mutant analysis, viral infection assays","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro ubiquitination assay, active-site mutagenesis, genetic KO/KD with clear viral phenotype, multiple orthogonal methods","pmids":["29899090"],"is_preprint":false},{"year":2018,"finding":"TRIM41/RINCK binds to cGAS and promotes monoubiquitination of cGAS, positively regulating cGAS-mediated cGAMP synthesis and downstream type I interferon production. CRISPR/Cas9 deletion of RINCK dampened interferon production in response to cytosolic DNA and HSV-1 infection, and reduced TBK1 and IRF3 phosphorylation.","method":"CRISPR/Cas9 deletion, co-immunoprecipitation, ubiquitination assay, cGAMP measurement, TBK1/IRF3 phosphorylation assay, viral infection with IFN readout","journal":"Cell & bioscience","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — reciprocal Co-IP, genetic KO, ubiquitination assay, multiple signaling readouts in single study","pmids":["29760876"],"is_preprint":false},{"year":2018,"finding":"TRIM41 acts as an E3 ubiquitin ligase for the transcription factor ZSCAN21, promoting its degradation and thereby reducing SNCA (α-synuclein) transcription in neuronal cells. TRIM17 antagonizes this pathway by decreasing TRIM41-mediated degradation of ZSCAN21. TRIM41 knockdown increased SNCA expression, while ZSCAN21 silencing and TRIM17 silencing both reduced it.","method":"siRNA knockdown, co-immunoprecipitation, ubiquitination assay, gene expression analysis, patient variant functional assay","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, ubiquitination assay, genetic knockdown with mRNA and protein readouts, multiple orthogonal methods, single lab","pmids":["30485814"],"is_preprint":false},{"year":2020,"finding":"TRIM41 interacts with and ubiquitinates the nucleoprotein (N) of vesicular stomatitis virus (VSV), leading to proteasomal degradation of VSV-N and restriction of VSV infection. An E3 ligase-defective TRIM41 mutant failed to limit VSV infection, confirming that ubiquitin ligase activity is required.","method":"Co-immunoprecipitation, in vitro and cellular ubiquitination assay, TRIM41 overexpression and knockdown, E3 ligase-dead mutant, viral infection assay with proteasome inhibitor","journal":"Viruses","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro ubiquitination, active-site mutagenesis, KD/KO with viral phenotype, multiple orthogonal methods, single lab","pmids":["31979016"],"is_preprint":false},{"year":2021,"finding":"TRIM41 directly interacts with BCL10, a core component of the CBM (CARD-BCL10-MALT1) complex, and catalyzes K63-linked polyubiquitination of BCL10. This K63-ubiquitination of BCL10 recruits NEMO, leading to activation of NF-κB and the TBK1-IRF3 pathway downstream of nucleic acid sensing, and is required for innate antiviral cytokine and interferon production.","method":"Co-immunoprecipitation, ubiquitination assay (K63 linkage-specific), TRIM41 knockout mice (in vivo), macrophage nucleic acid transfection and viral infection assays, cytokine/IFN measurement, NF-κB/TBK1/IRF3 activation readouts","journal":"Signal transduction and targeted therapy","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, linkage-specific ubiquitination assay, in vivo KO, multiple pathway readouts, single lab","pmids":["33640899"],"is_preprint":false},{"year":2021,"finding":"TRIM41 targets PKD1 for ubiquitin-mediated degradation; ANXA10 interacts with PKD1 and protects it from TRIM41-directed degradation. In melanoma cells, ANXA10-mediated stabilization of PKD1 suppresses SMAD6 expression (via TGF-β/SMAD pathway) to promote cell migration and metastasis.","method":"Co-immunoprecipitation, protein stability assay, ANXA10 knockout, ubiquitination assay (inferred), cell migration and in vivo metastasis assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and genetic KO with phenotypic readout, ubiquitination mechanism not directly reconstituted in vitro in abstract, single lab","pmids":["34324862"],"is_preprint":false},{"year":2022,"finding":"TRIM41 is required for proper meiotic progression in male mice. Trim41 knockout spermatocytes exhibit overloading of SYCP3 on chromosome axes, particularly the X chromosome. A RING-domain deletion mutant of TRIM41 (which abolishes E3 ubiquitin ligase activity) phenocopies the full knockout, and mutant ΔRING-TRIM41 accumulates on chromosome axes with overloaded SYCP3, indicating TRIM41 regulates chromosome axis protein dynamics via its E3 ligase activity.","method":"Trim41 knockout mice, RING-domain deletion knock-in mutant mice, immunofluorescence of meiotic chromosome spreads for SYCP3, fertility assays","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO and domain-specific knock-in mutant with clear meiotic phenotype and mechanistic domain dissection in vivo, single lab","pmids":["35648791"],"is_preprint":false},{"year":2023,"finding":"TRIM41 interacts with LINE-1 ORF2p and ubiquitinates it, promoting its proteasomal degradation and suppressing L1 retrotransposition. Nuclear cGAS enhances the association between ORF2p and TRIM41, thereby promoting TRIM41-mediated ORF2p degradation. Upon DNA damage, CHK2 phosphorylates cGAS at S120 and S305, which strengthens cGAS-TRIM41 association and further promotes ORF2p degradation.","method":"Co-immunoprecipitation, ubiquitination assay, TRIM41 knockdown, L1 retrotransposition reporter assay, phospho-mutant analysis, cancer-associated cGAS variant functional analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, ubiquitination assay, genetic KD with functional retrotransposition readout, multiple mutant validations, single lab with multiple orthogonal methods","pmids":["38086852"],"is_preprint":false},{"year":2023,"finding":"TRIM41/RINCK directly interacts with NRF2 and promotes its K48-linked polyubiquitination and proteasomal degradation in intestinal epithelial cells, suppressing NRF2 nuclear translocation and downstream antioxidant gene expression. IEC-specific Rinck knockout mitigated OTA/DSS-induced colitis and associated early colorectal cancer in mice.","method":"Co-immunoprecipitation, K48-linkage ubiquitination assay, IEC-specific Rinck knockout and overexpression transgenic mice, AAV-mediated knockdown, lentiviral knockdown, NRF2 nuclear localization assay, in vivo colitis and tumor models","journal":"Phytomedicine","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, K48-specific ubiquitination assay, multiple in vivo genetic models with clear phenotype, single lab","pmids":["37844381"],"is_preprint":false},{"year":2023,"finding":"circRNA_0067717 acts as a molecular scaffold that bridges TRIM41 and p53, promoting TRIM41-mediated ubiquitination and degradation of p53 in NPC paclitaxel-resistant cells. The 301–425 nt region of circRNA_0067717 binds TRIM41 and the 1–176 nt region binds p53. Blocking these regions reduced paclitaxel resistance.","method":"RNA pulldown, RNA immunoprecipitation, RNA FISH, siRNA knockdown, ubiquitination assay, deletion mapping of circRNA binding sites","journal":"Cellular oncology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — RNA pulldown and RIP establish scaffold interaction; ubiquitination of p53 by TRIM41 shown in cellular context; single lab, mechanistic role of TRIM41 itself not reconstituted independently of circRNA scaffold","pmids":["36705889"],"is_preprint":false},{"year":2024,"finding":"TRIM41 promotes the ubiquitination and degradation of c-Maf in airway dendritic cells, reducing IL-10 expression and compromising tolerogenic DC properties, thereby contributing to airway allergy pathogenesis.","method":"Trim41 overexpression and inhibition in DCs, c-Maf protein level assay, IL-10 expression assay, murine airway allergy model","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single lab, cellular overexpression/inhibition with protein level and cytokine readout; direct ubiquitination assay for c-Maf not explicitly described in abstract","pmids":["38883815"],"is_preprint":false}],"current_model":"TRIM41 (also known as RINCK) is a TRIM-family E3 ubiquitin ligase whose RING domain catalyzes ubiquitination of diverse substrates—including PKC isoforms (via their C1A domain), viral nucleoproteins (IAV NP, VSV N), cGAS (monoubiquitination promoting cGAMP synthesis), BCL10 (K63-linked, recruiting NEMO for NF-κB/TBK1-IRF3 activation), ZSCAN21 (controlling α-synuclein transcription), ORF2p (suppressing L1 retrotransposition in concert with nuclear cGAS), NRF2 (K48-linked degradation in intestinal cells), c-Maf (in dendritic cells), p53 (scaffolded by circRNA_0067717), and PKD1—leading predominantly to proteasomal degradation of substrates; the protein localizes to cytoplasmic and nuclear speckles via an N-terminal nuclear transport signal, and its E3 ligase activity is required for all described antiviral, meiotic, and immune regulatory functions."},"narrative":{"mechanistic_narrative":"TRIM41 (RINCK) is a TRIM-family RING E3 ubiquitin ligase that acts as a substrate-selective controller of protein abundance across antiviral defense, immune signaling, redox homeostasis, transcriptional control, and meiosis, with its E3 ligase activity required for these functions [PMID:17893151, PMID:29899090, PMID:35648791]. It was first defined through its substrate-recognition C1A-domain interaction with all classes of protein kinase C, which it ubiquitinates to drive PKC degradation independently of phorbol-ester downregulation [PMID:17893151]. In antiviral restriction, TRIM41 binds viral nucleoproteins—influenza A virus NP via its SPRY domain and VSV N protein—and targets them for polyubiquitination and proteasomal degradation, with RING-dead mutants abolishing restriction [PMID:29899090, PMID:31979016]. TRIM41 also positively shapes innate immune signaling: it monoubiquitinates cGAS to enhance cGAMP synthesis and type I interferon output [PMID:29760876], and catalyzes K63-linked ubiquitination of BCL10 within the CBM complex to recruit NEMO and activate NF-κB and the TBK1–IRF3 axis [PMID:33640899]. Through K48-linked degradative ubiquitination it controls additional substrates, including NRF2 to restrain antioxidant gene expression in intestinal epithelium [PMID:37844381], the transcription factor ZSCAN21 to limit α-synuclein (SNCA) transcription [PMID:30485814], LINE-1 ORF2p to suppress retrotransposition in a nuclear-cGAS-assisted manner [PMID:38086852], and PKD1, p53, and c-Maf in various cellular contexts [PMID:34324862, PMID:36705889, PMID:38883815]. In vivo, TRIM41 is required for male meiotic progression, where its RING activity regulates SYCP3 loading dynamics on chromosome axes [PMID:35648791].","teleology":[{"year":2005,"claim":"Established where TRIM41 protein resides and that an N-terminal segment governs its trafficking, framing it as a dual cytoplasmic/nuclear factor before any catalytic role was known.","evidence":"GFP-fusion live imaging of truncation mutants and subcellular fractionation","pmids":["16022281"],"confidence":"Medium","gaps":["Functional consequence of speckle localization unknown","NLS-independent nuclear transport mechanism not resolved","Single lab, descriptive"]},{"year":2007,"claim":"Defined TRIM41 as a bona fide E3 ubiquitin ligase and identified its first substrate, showing it targets PKC isozymes via their C1A domain for degradation independently of phorbol-ester-induced turnover.","evidence":"Yeast two-hybrid, co-IP, in vitro and cellular ubiquitination assays, siRNA/overexpression","pmids":["17893151"],"confidence":"High","gaps":["Ubiquitin linkage type on PKC not defined","Physiological context of PKC regulation unclear","RING-dependence not formally tested here"]},{"year":2018,"claim":"Revealed an antiviral function: TRIM41 recognizes influenza A NP through its SPRY domain and degrades it, with RING activity required for restriction, establishing a substrate-recognition-domain architecture.","evidence":"Co-IP, in vitro ubiquitination, RNAi/CRISPR KO, E3-dead mutant, IAV infection assays","pmids":["29899090"],"confidence":"High","gaps":["Generality across viral nucleoproteins not yet shown","In vivo relevance untested"]},{"year":2018,"claim":"Showed TRIM41 can act as a positive immune regulator via non-degradative ubiquitination, monoubiquitinating cGAS to enhance cGAMP synthesis and interferon induction.","evidence":"CRISPR KO, co-IP, ubiquitination assay, cGAMP measurement, TBK1/IRF3 phospho-readouts, HSV-1 infection","pmids":["29760876"],"confidence":"High","gaps":["Monoubiquitination site on cGAS not mapped","Relationship to TRIM41's degradative activity unclear"]},{"year":2018,"claim":"Connected TRIM41 to transcriptional control of α-synuclein by degrading ZSCAN21, and placed it in an antagonistic relationship with TRIM17.","evidence":"siRNA, reciprocal co-IP, ubiquitination assay, SNCA mRNA readout, patient variant assay","pmids":["30485814"],"confidence":"High","gaps":["Neuronal phenotype in vivo not established","Disease causation not demonstrated"]},{"year":2020,"claim":"Extended the antiviral nucleoprotein-degradation paradigm to VSV N protein, reinforcing RING-dependent restriction of negative-strand RNA viruses.","evidence":"Co-IP, in vitro/cellular ubiquitination, KD/OE, E3-dead mutant, infection with proteasome inhibitor","pmids":["31979016"],"confidence":"High","gaps":["Ubiquitin linkage on VSV N not defined","Breadth of viral nucleoprotein targeting unknown"]},{"year":2021,"claim":"Identified BCL10 as a K63-ubiquitination substrate, showing TRIM41 drives NEMO recruitment and NF-κB/TBK1–IRF3 activation downstream of nucleic-acid sensing, validated in knockout mice.","evidence":"Reciprocal co-IP, K63-linkage-specific ubiquitination assay, Trim41 KO mice, macrophage stimulation/infection, cytokine readouts","pmids":["33640899"],"confidence":"High","gaps":["K63 chain assembly mechanism on BCL10 not structurally resolved","Interplay with cGAS-monoubiquitination role unclear"]},{"year":2021,"claim":"Placed TRIM41 in a cancer-relevant degradation axis by targeting PKD1, antagonized by ANXA10, linking it to TGF-β/SMAD signaling and melanoma metastasis.","evidence":"Co-IP, protein stability assay, ANXA10 KO, migration and in vivo metastasis assays","pmids":["34324862"],"confidence":"Medium","gaps":["Direct in vitro ubiquitination of PKD1 not reconstituted","Ubiquitin linkage type undefined","Single lab"]},{"year":2022,"claim":"Demonstrated a physiological in vivo role in male meiosis, where RING activity controls SYCP3 loading on chromosome axes, with a RING-deletion knock-in phenocopying full knockout.","evidence":"Trim41 KO and RING-deletion knock-in mice, meiotic chromosome-spread immunofluorescence, fertility assays","pmids":["35648791"],"confidence":"High","gaps":["Whether SYCP3 is a direct ubiquitination substrate not shown","Mechanism of axis recruitment unresolved"]},{"year":2023,"claim":"Showed TRIM41 suppresses LINE-1 retrotransposition by degrading ORF2p, with nuclear cGAS and CHK2-driven cGAS phosphorylation enhancing the TRIM41–ORF2p association upon DNA damage.","evidence":"Co-IP, ubiquitination assay, KD, L1 retrotransposition reporter, phospho-mutant and cancer-variant analysis","pmids":["38086852"],"confidence":"High","gaps":["Structural basis of cGAS-enhanced recruitment unknown","ORF2p ubiquitination sites not mapped"]},{"year":2023,"claim":"Established TRIM41 as a negative regulator of NRF2 via K48-linked degradation in intestinal epithelium, with loss protecting against colitis and early colorectal cancer in vivo.","evidence":"Reciprocal co-IP, K48-linkage ubiquitination assay, IEC-specific KO/OE mice, AAV/lentiviral KD, colitis/tumor models","pmids":["37844381"],"confidence":"High","gaps":["NRF2 ubiquitination sites not defined","Tissue specificity of this regulation not explained"]},{"year":2023,"claim":"Showed circRNA_0067717 scaffolds TRIM41 to p53, enabling p53 degradation and paclitaxel resistance, illustrating RNA-directed substrate selection.","evidence":"RNA pulldown, RIP, FISH, siRNA, ubiquitination assay, circRNA deletion mapping","pmids":["36705889"],"confidence":"Medium","gaps":["TRIM41 activity on p53 not shown independent of the circRNA scaffold","Direct p53 ubiquitination linkage undefined","Single lab"]},{"year":2024,"claim":"Linked TRIM41 to immune tolerance by degrading c-Maf in airway dendritic cells, reducing IL-10 and promoting allergy.","evidence":"Trim41 OE/inhibition in DCs, c-Maf and IL-10 readouts, murine airway allergy model","pmids":["38883815"],"confidence":"Medium","gaps":["Direct ubiquitination assay for c-Maf not described","Single lab, cellular manipulation only"]},{"year":null,"claim":"How TRIM41 selects among its diverse substrates and switches between K48-degradative, K63-signaling, and monoubiquitination outputs remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of substrate or chain-type selection","Determinants directing degradative vs signaling ubiquitination unknown","Regulation of TRIM41 abundance/activity uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,2,5,6,8,10]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,3,5,6,10]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,3,5,6,12]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,2,5,6,10]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[8]}],"complexes":[],"partners":["PRKCB","CGAS","BCL10","ZSCAN21","NRF2","PKD1","TP53","ORF2P"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8WV44","full_name":"E3 ubiquitin-protein ligase TRIM41","aliases":["RING finger-interacting protein with C kinase","RINCK","Tripartite motif-containing protein 41"],"length_aa":630,"mass_kda":71.7,"function":"E3 ligase that plays essential roles in innate antiviral response (PubMed:28169297, PubMed:29760876, PubMed:29899090, PubMed:31979016). Directly binds to influenza A virus or vesicular stomatitis virus nucleoproteins and targets them for ubiquitination and proteasomal degradation, thereby limiting viral infections (PubMed:28169297, PubMed:29899090, PubMed:31979016). Activates the innate antiviral response by catalyzing monoubiquitination of CGAS, thereby activating CGAS (PubMed:29760876). Also involved in innate antiviral response by mediating 'Lys-63'-linked polyubiquitylation of BCL10 which in turn hubs NEMO for activation of NF-kappa-B and IRF3 pathways (By similarity). Catalyzes the ubiquitin-mediated degradation of other substrates including protein kinase C, ZSCAN21 or TOP3B suggesting additional roles besides its function in immune response (PubMed:17893151, PubMed:33378676)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q8WV44/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TRIM41","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TRIM41","total_profiled":1310},"omim":[{"mim_id":"619265","title":"TRIPARTITE MOTIF-CONTAINING PROTEIN 52; TRIM52","url":"https://www.omim.org/entry/619265"},{"mim_id":"610530","title":"TRIPARTITE MOTIF-CONTAINING PROTEIN 41; TRIM41","url":"https://www.omim.org/entry/610530"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoli fibrillar center","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Vesicles","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":76.8},{"tissue":"skeletal muscle","ntpm":24.4}],"url":"https://www.proteinatlas.org/search/TRIM41"},"hgnc":{"alias_symbol":["MGC1127","RINCK"],"prev_symbol":[]},"alphafold":{"accession":"Q8WV44","domains":[{"cath_id":"3.30.40.10","chopping":"10-51_179-218","consensus_level":"medium","plddt":80.4718,"start":10,"end":218},{"cath_id":"2.60.120.920","chopping":"428-507_547-630","consensus_level":"high","plddt":88.9041,"start":428,"end":630}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WV44","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WV44-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WV44-F1-predicted_aligned_error_v6.png","plddt_mean":72.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TRIM41","jax_strain_url":"https://www.jax.org/strain/search?query=TRIM41"},"sequence":{"accession":"Q8WV44","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8WV44.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8WV44/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WV44"}},"corpus_meta":[{"pmid":"29899090","id":"PMC_29899090","title":"TRIM41-Mediated Ubiquitination of Nucleoprotein Limits Influenza A Virus Infection.","date":"2018","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/29899090","citation_count":77,"is_preprint":false},{"pmid":"29760876","id":"PMC_29760876","title":"RINCK-mediated monoubiquitination of cGAS promotes antiviral innate immune responses.","date":"2018","source":"Cell & bioscience","url":"https://pubmed.ncbi.nlm.nih.gov/29760876","citation_count":56,"is_preprint":false},{"pmid":"17893151","id":"PMC_17893151","title":"Amplitude control of protein kinase C by RINCK, a novel E3 ubiquitin ligase.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17893151","citation_count":53,"is_preprint":false},{"pmid":"38086852","id":"PMC_38086852","title":"Nuclear cGAS restricts L1 retrotransposition by promoting TRIM41-mediated ORF2p ubiquitination and degradation.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/38086852","citation_count":38,"is_preprint":false},{"pmid":"30485814","id":"PMC_30485814","title":"The E3 Ubiquitin Ligases TRIM17 and TRIM41 Modulate α-Synuclein Expression by Regulating ZSCAN21.","date":"2018","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/30485814","citation_count":35,"is_preprint":false},{"pmid":"31979016","id":"PMC_31979016","title":"TRIM41-Mediated Ubiquitination of Nucleoprotein Limits Vesicular Stomatitis Virus Infection.","date":"2020","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/31979016","citation_count":24,"is_preprint":false},{"pmid":"33640899","id":"PMC_33640899","title":"TRIM41 is required to innate antiviral response by polyubiquitinating BCL10 and recruiting NEMO.","date":"2021","source":"Signal transduction and targeted therapy","url":"https://pubmed.ncbi.nlm.nih.gov/33640899","citation_count":22,"is_preprint":false},{"pmid":"36705889","id":"PMC_36705889","title":"circRNA_0067717 promotes paclitaxel resistance in nasopharyngeal carcinoma by acting as a scaffold for TRIM41 and p53.","date":"2023","source":"Cellular oncology (Dordrecht, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/36705889","citation_count":20,"is_preprint":false},{"pmid":"34324862","id":"PMC_34324862","title":"ANXA10 promotes melanoma metastasis by suppressing E3 ligase TRIM41-directed PKD1 degradation.","date":"2021","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/34324862","citation_count":19,"is_preprint":false},{"pmid":"37844381","id":"PMC_37844381","title":"Ochratoxin A promotes chronic enteritis and early colorectal cancer progression by targeting Rinck signaling.","date":"2023","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/37844381","citation_count":13,"is_preprint":false},{"pmid":"16022281","id":"PMC_16022281","title":"Intracellular localization and domain organization of human TRIM41 proteins.","date":"2005","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/16022281","citation_count":7,"is_preprint":false},{"pmid":"35648791","id":"PMC_35648791","title":"Trim41 is required to regulate chromosome axis protein dynamics and meiosis in male mice.","date":"2022","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35648791","citation_count":1,"is_preprint":false},{"pmid":"38883815","id":"PMC_38883815","title":"TRIM41 contributes to the pathogenesis of airway allergy by compromising dendritic cells' tolerogenic properties.","date":"2024","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/38883815","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8788,"output_tokens":3769,"usd":0.04145,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11520,"output_tokens":4199,"usd":0.081287,"stage2_stop_reason":"end_turn"},"total_usd":0.122737,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"TRIM41/RINCK was identified as an E3 ubiquitin ligase that interacts with protein kinase C (PKC) via the C1A domain of PKC (identified by yeast two-hybrid with PKCβ N-terminus as bait). TRIM41 ubiquitinates PKC both in vitro and in cells, leading to PKC degradation and reduced PKC levels; this mechanism is independent of phorbol ester-mediated PKC downregulation and applies to conventional, novel, and atypical PKC isozymes.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, in vitro and cellular ubiquitination assay, overexpression and siRNA knockdown with PKC level readout\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro ubiquitination assay plus cellular co-IP and genetic knockdown/overexpression with multiple orthogonal methods in one study\",\n      \"pmids\": [\"17893151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TRIM41 protein (isoforms alpha and beta) localizes as speckles in both cytoplasm and nucleus of cells. Nuclear transport is mediated by an N-terminal segment common to both isoforms but is independent of a classical nuclear localization signal sequence, as determined by GFP fusion constructs and subcellular fractionation.\",\n      \"method\": \"GFP fusion live-cell imaging of truncation mutants, Western blot of cellular fractions\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — direct localization by GFP fusions with domain mapping and fractionation validation, single lab\",\n      \"pmids\": [\"16022281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TRIM41 interacts with influenza A virus nucleoprotein (NP) through its SPRY domain, ubiquitinates NP in vitro and in cells, and promotes NP polyubiquitination and proteasomal degradation, thereby restricting IAV infection. A TRIM41 RING-domain mutant lacking E3 ligase activity failed to inhibit IAV infection, demonstrating that E3 ligase activity is essential for antiviral function.\",\n      \"method\": \"Co-immunoprecipitation, in vitro ubiquitination assay, RNAi knockdown and CRISPR knockout of TRIM41, TRIM41 overexpression, E3 ligase-dead mutant analysis, viral infection assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro ubiquitination assay, active-site mutagenesis, genetic KO/KD with clear viral phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"29899090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TRIM41/RINCK binds to cGAS and promotes monoubiquitination of cGAS, positively regulating cGAS-mediated cGAMP synthesis and downstream type I interferon production. CRISPR/Cas9 deletion of RINCK dampened interferon production in response to cytosolic DNA and HSV-1 infection, and reduced TBK1 and IRF3 phosphorylation.\",\n      \"method\": \"CRISPR/Cas9 deletion, co-immunoprecipitation, ubiquitination assay, cGAMP measurement, TBK1/IRF3 phosphorylation assay, viral infection with IFN readout\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — reciprocal Co-IP, genetic KO, ubiquitination assay, multiple signaling readouts in single study\",\n      \"pmids\": [\"29760876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TRIM41 acts as an E3 ubiquitin ligase for the transcription factor ZSCAN21, promoting its degradation and thereby reducing SNCA (α-synuclein) transcription in neuronal cells. TRIM17 antagonizes this pathway by decreasing TRIM41-mediated degradation of ZSCAN21. TRIM41 knockdown increased SNCA expression, while ZSCAN21 silencing and TRIM17 silencing both reduced it.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation, ubiquitination assay, gene expression analysis, patient variant functional assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, ubiquitination assay, genetic knockdown with mRNA and protein readouts, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"30485814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRIM41 interacts with and ubiquitinates the nucleoprotein (N) of vesicular stomatitis virus (VSV), leading to proteasomal degradation of VSV-N and restriction of VSV infection. An E3 ligase-defective TRIM41 mutant failed to limit VSV infection, confirming that ubiquitin ligase activity is required.\",\n      \"method\": \"Co-immunoprecipitation, in vitro and cellular ubiquitination assay, TRIM41 overexpression and knockdown, E3 ligase-dead mutant, viral infection assay with proteasome inhibitor\",\n      \"journal\": \"Viruses\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro ubiquitination, active-site mutagenesis, KD/KO with viral phenotype, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"31979016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIM41 directly interacts with BCL10, a core component of the CBM (CARD-BCL10-MALT1) complex, and catalyzes K63-linked polyubiquitination of BCL10. This K63-ubiquitination of BCL10 recruits NEMO, leading to activation of NF-κB and the TBK1-IRF3 pathway downstream of nucleic acid sensing, and is required for innate antiviral cytokine and interferon production.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K63 linkage-specific), TRIM41 knockout mice (in vivo), macrophage nucleic acid transfection and viral infection assays, cytokine/IFN measurement, NF-κB/TBK1/IRF3 activation readouts\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, linkage-specific ubiquitination assay, in vivo KO, multiple pathway readouts, single lab\",\n      \"pmids\": [\"33640899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIM41 targets PKD1 for ubiquitin-mediated degradation; ANXA10 interacts with PKD1 and protects it from TRIM41-directed degradation. In melanoma cells, ANXA10-mediated stabilization of PKD1 suppresses SMAD6 expression (via TGF-β/SMAD pathway) to promote cell migration and metastasis.\",\n      \"method\": \"Co-immunoprecipitation, protein stability assay, ANXA10 knockout, ubiquitination assay (inferred), cell migration and in vivo metastasis assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and genetic KO with phenotypic readout, ubiquitination mechanism not directly reconstituted in vitro in abstract, single lab\",\n      \"pmids\": [\"34324862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM41 is required for proper meiotic progression in male mice. Trim41 knockout spermatocytes exhibit overloading of SYCP3 on chromosome axes, particularly the X chromosome. A RING-domain deletion mutant of TRIM41 (which abolishes E3 ubiquitin ligase activity) phenocopies the full knockout, and mutant ΔRING-TRIM41 accumulates on chromosome axes with overloaded SYCP3, indicating TRIM41 regulates chromosome axis protein dynamics via its E3 ligase activity.\",\n      \"method\": \"Trim41 knockout mice, RING-domain deletion knock-in mutant mice, immunofluorescence of meiotic chromosome spreads for SYCP3, fertility assays\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO and domain-specific knock-in mutant with clear meiotic phenotype and mechanistic domain dissection in vivo, single lab\",\n      \"pmids\": [\"35648791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIM41 interacts with LINE-1 ORF2p and ubiquitinates it, promoting its proteasomal degradation and suppressing L1 retrotransposition. Nuclear cGAS enhances the association between ORF2p and TRIM41, thereby promoting TRIM41-mediated ORF2p degradation. Upon DNA damage, CHK2 phosphorylates cGAS at S120 and S305, which strengthens cGAS-TRIM41 association and further promotes ORF2p degradation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, TRIM41 knockdown, L1 retrotransposition reporter assay, phospho-mutant analysis, cancer-associated cGAS variant functional analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, ubiquitination assay, genetic KD with functional retrotransposition readout, multiple mutant validations, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"38086852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIM41/RINCK directly interacts with NRF2 and promotes its K48-linked polyubiquitination and proteasomal degradation in intestinal epithelial cells, suppressing NRF2 nuclear translocation and downstream antioxidant gene expression. IEC-specific Rinck knockout mitigated OTA/DSS-induced colitis and associated early colorectal cancer in mice.\",\n      \"method\": \"Co-immunoprecipitation, K48-linkage ubiquitination assay, IEC-specific Rinck knockout and overexpression transgenic mice, AAV-mediated knockdown, lentiviral knockdown, NRF2 nuclear localization assay, in vivo colitis and tumor models\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, K48-specific ubiquitination assay, multiple in vivo genetic models with clear phenotype, single lab\",\n      \"pmids\": [\"37844381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"circRNA_0067717 acts as a molecular scaffold that bridges TRIM41 and p53, promoting TRIM41-mediated ubiquitination and degradation of p53 in NPC paclitaxel-resistant cells. The 301–425 nt region of circRNA_0067717 binds TRIM41 and the 1–176 nt region binds p53. Blocking these regions reduced paclitaxel resistance.\",\n      \"method\": \"RNA pulldown, RNA immunoprecipitation, RNA FISH, siRNA knockdown, ubiquitination assay, deletion mapping of circRNA binding sites\",\n      \"journal\": \"Cellular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — RNA pulldown and RIP establish scaffold interaction; ubiquitination of p53 by TRIM41 shown in cellular context; single lab, mechanistic role of TRIM41 itself not reconstituted independently of circRNA scaffold\",\n      \"pmids\": [\"36705889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM41 promotes the ubiquitination and degradation of c-Maf in airway dendritic cells, reducing IL-10 expression and compromising tolerogenic DC properties, thereby contributing to airway allergy pathogenesis.\",\n      \"method\": \"Trim41 overexpression and inhibition in DCs, c-Maf protein level assay, IL-10 expression assay, murine airway allergy model\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, cellular overexpression/inhibition with protein level and cytokine readout; direct ubiquitination assay for c-Maf not explicitly described in abstract\",\n      \"pmids\": [\"38883815\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TRIM41 (also known as RINCK) is a TRIM-family E3 ubiquitin ligase whose RING domain catalyzes ubiquitination of diverse substrates—including PKC isoforms (via their C1A domain), viral nucleoproteins (IAV NP, VSV N), cGAS (monoubiquitination promoting cGAMP synthesis), BCL10 (K63-linked, recruiting NEMO for NF-κB/TBK1-IRF3 activation), ZSCAN21 (controlling α-synuclein transcription), ORF2p (suppressing L1 retrotransposition in concert with nuclear cGAS), NRF2 (K48-linked degradation in intestinal cells), c-Maf (in dendritic cells), p53 (scaffolded by circRNA_0067717), and PKD1—leading predominantly to proteasomal degradation of substrates; the protein localizes to cytoplasmic and nuclear speckles via an N-terminal nuclear transport signal, and its E3 ligase activity is required for all described antiviral, meiotic, and immune regulatory functions.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TRIM41 (RINCK) is a TRIM-family RING E3 ubiquitin ligase that acts as a substrate-selective controller of protein abundance across antiviral defense, immune signaling, redox homeostasis, transcriptional control, and meiosis, with its E3 ligase activity required for these functions [#0, #2, #8]. It was first defined through its substrate-recognition C1A-domain interaction with all classes of protein kinase C, which it ubiquitinates to drive PKC degradation independently of phorbol-ester downregulation [#0]. In antiviral restriction, TRIM41 binds viral nucleoproteins\\u2014influenza A virus NP via its SPRY domain and VSV N protein\\u2014and targets them for polyubiquitination and proteasomal degradation, with RING-dead mutants abolishing restriction [#2, #5]. TRIM41 also positively shapes innate immune signaling: it monoubiquitinates cGAS to enhance cGAMP synthesis and type I interferon output [#3], and catalyzes K63-linked ubiquitination of BCL10 within the CBM complex to recruit NEMO and activate NF-\\u03baB and the TBK1\\u2013IRF3 axis [#6]. Through K48-linked degradative ubiquitination it controls additional substrates, including NRF2 to restrain antioxidant gene expression in intestinal epithelium [#10], the transcription factor ZSCAN21 to limit \\u03b1-synuclein (SNCA) transcription [#4], LINE-1 ORF2p to suppress retrotransposition in a nuclear-cGAS-assisted manner [#9], and PKD1, p53, and c-Maf in various cellular contexts [#7, #11, #12]. In vivo, TRIM41 is required for male meiotic progression, where its RING activity regulates SYCP3 loading dynamics on chromosome axes [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established where TRIM41 protein resides and that an N-terminal segment governs its trafficking, framing it as a dual cytoplasmic/nuclear factor before any catalytic role was known.\",\n      \"evidence\": \"GFP-fusion live imaging of truncation mutants and subcellular fractionation\",\n      \"pmids\": [\"16022281\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of speckle localization unknown\", \"NLS-independent nuclear transport mechanism not resolved\", \"Single lab, descriptive\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined TRIM41 as a bona fide E3 ubiquitin ligase and identified its first substrate, showing it targets PKC isozymes via their C1A domain for degradation independently of phorbol-ester-induced turnover.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, in vitro and cellular ubiquitination assays, siRNA/overexpression\",\n      \"pmids\": [\"17893151\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitin linkage type on PKC not defined\", \"Physiological context of PKC regulation unclear\", \"RING-dependence not formally tested here\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed an antiviral function: TRIM41 recognizes influenza A NP through its SPRY domain and degrades it, with RING activity required for restriction, establishing a substrate-recognition-domain architecture.\",\n      \"evidence\": \"Co-IP, in vitro ubiquitination, RNAi/CRISPR KO, E3-dead mutant, IAV infection assays\",\n      \"pmids\": [\"29899090\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality across viral nucleoproteins not yet shown\", \"In vivo relevance untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed TRIM41 can act as a positive immune regulator via non-degradative ubiquitination, monoubiquitinating cGAS to enhance cGAMP synthesis and interferon induction.\",\n      \"evidence\": \"CRISPR KO, co-IP, ubiquitination assay, cGAMP measurement, TBK1/IRF3 phospho-readouts, HSV-1 infection\",\n      \"pmids\": [\"29760876\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Monoubiquitination site on cGAS not mapped\", \"Relationship to TRIM41's degradative activity unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected TRIM41 to transcriptional control of \\u03b1-synuclein by degrading ZSCAN21, and placed it in an antagonistic relationship with TRIM17.\",\n      \"evidence\": \"siRNA, reciprocal co-IP, ubiquitination assay, SNCA mRNA readout, patient variant assay\",\n      \"pmids\": [\"30485814\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Neuronal phenotype in vivo not established\", \"Disease causation not demonstrated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended the antiviral nucleoprotein-degradation paradigm to VSV N protein, reinforcing RING-dependent restriction of negative-strand RNA viruses.\",\n      \"evidence\": \"Co-IP, in vitro/cellular ubiquitination, KD/OE, E3-dead mutant, infection with proteasome inhibitor\",\n      \"pmids\": [\"31979016\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitin linkage on VSV N not defined\", \"Breadth of viral nucleoprotein targeting unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified BCL10 as a K63-ubiquitination substrate, showing TRIM41 drives NEMO recruitment and NF-\\u03baB/TBK1\\u2013IRF3 activation downstream of nucleic-acid sensing, validated in knockout mice.\",\n      \"evidence\": \"Reciprocal co-IP, K63-linkage-specific ubiquitination assay, Trim41 KO mice, macrophage stimulation/infection, cytokine readouts\",\n      \"pmids\": [\"33640899\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"K63 chain assembly mechanism on BCL10 not structurally resolved\", \"Interplay with cGAS-monoubiquitination role unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed TRIM41 in a cancer-relevant degradation axis by targeting PKD1, antagonized by ANXA10, linking it to TGF-\\u03b2/SMAD signaling and melanoma metastasis.\",\n      \"evidence\": \"Co-IP, protein stability assay, ANXA10 KO, migration and in vivo metastasis assays\",\n      \"pmids\": [\"34324862\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct in vitro ubiquitination of PKD1 not reconstituted\", \"Ubiquitin linkage type undefined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated a physiological in vivo role in male meiosis, where RING activity controls SYCP3 loading on chromosome axes, with a RING-deletion knock-in phenocopying full knockout.\",\n      \"evidence\": \"Trim41 KO and RING-deletion knock-in mice, meiotic chromosome-spread immunofluorescence, fertility assays\",\n      \"pmids\": [\"35648791\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SYCP3 is a direct ubiquitination substrate not shown\", \"Mechanism of axis recruitment unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed TRIM41 suppresses LINE-1 retrotransposition by degrading ORF2p, with nuclear cGAS and CHK2-driven cGAS phosphorylation enhancing the TRIM41\\u2013ORF2p association upon DNA damage.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, KD, L1 retrotransposition reporter, phospho-mutant and cancer-variant analysis\",\n      \"pmids\": [\"38086852\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of cGAS-enhanced recruitment unknown\", \"ORF2p ubiquitination sites not mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established TRIM41 as a negative regulator of NRF2 via K48-linked degradation in intestinal epithelium, with loss protecting against colitis and early colorectal cancer in vivo.\",\n      \"evidence\": \"Reciprocal co-IP, K48-linkage ubiquitination assay, IEC-specific KO/OE mice, AAV/lentiviral KD, colitis/tumor models\",\n      \"pmids\": [\"37844381\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"NRF2 ubiquitination sites not defined\", \"Tissue specificity of this regulation not explained\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed circRNA_0067717 scaffolds TRIM41 to p53, enabling p53 degradation and paclitaxel resistance, illustrating RNA-directed substrate selection.\",\n      \"evidence\": \"RNA pulldown, RIP, FISH, siRNA, ubiquitination assay, circRNA deletion mapping\",\n      \"pmids\": [\"36705889\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TRIM41 activity on p53 not shown independent of the circRNA scaffold\", \"Direct p53 ubiquitination linkage undefined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked TRIM41 to immune tolerance by degrading c-Maf in airway dendritic cells, reducing IL-10 and promoting allergy.\",\n      \"evidence\": \"Trim41 OE/inhibition in DCs, c-Maf and IL-10 readouts, murine airway allergy model\",\n      \"pmids\": [\"38883815\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ubiquitination assay for c-Maf not described\", \"Single lab, cellular manipulation only\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TRIM41 selects among its diverse substrates and switches between K48-degradative, K63-signaling, and monoubiquitination outputs remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of substrate or chain-type selection\", \"Determinants directing degradative vs signaling ubiquitination unknown\", \"Regulation of TRIM41 abundance/activity uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 2, 5, 6, 8, 10]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 3, 5, 6, 10]},\n      {\"term_id\": \"GO:0061630\", \"supporting_discovery_ids\": [0, 2, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 3, 5, 6, 12]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 2, 5, 6, 10]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PRKCB\", \"cGAS\", \"BCL10\", \"ZSCAN21\", \"NRF2\", \"PKD1\", \"TP53\", \"ORF2p\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}