{"gene":"LRRC41","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2001,"finding":"MUF1 (LRRC41) was purified from rat liver as a novel leucine-rich repeat-containing BC-box protein that interacts with Elongin BC and assembles with Cul5 and Rbx1 to reconstitute ubiquitin ligase activity in vitro.","method":"Protein purification from rat liver, in vitro reconstitution of ubiquitin ligase activity, BC-box motif identification","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of E3 ubiquitin ligase activity with purified components, biochemical purification from native tissue","pmids":["11384984"],"is_preprint":false},{"year":2012,"finding":"MUF1/LRRC41 is a predominantly nuclear, ubiquitously expressed dimeric protein that interacts with all three mammalian RhoBTB proteins (RhoBTB1, 2, 3) via immunoprecipitation; upon coexpression with RhoBTB, MUF1 partially relocates to the cytoplasm where both proteins colocalize.","method":"Yeast two-hybrid screening, co-immunoprecipitation, subcellular localization imaging","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and localization imaging, single lab, two orthogonal methods","pmids":["22709582"],"is_preprint":false},{"year":2012,"finding":"MUF1/LRRC41 is degraded by the proteasome via a Cul5-independent mechanism mediated by the RhoBTB3-Cul3 ubiquitin ligase complex, making MUF1 the first identified substrate of RhoBTB-Cul3 ubiquitin ligase complexes.","method":"Protein stability assay, proteasome inhibitor treatment, dominant-negative Cul3 expression","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — protein stability assay with mechanistic follow-up, single lab, multiple complementary approaches","pmids":["22709582"],"is_preprint":false},{"year":2012,"finding":"MUF1/LRRC41 is capable of homodimerization, consistent with other leucine-rich repeat-containing proteins.","method":"Co-immunoprecipitation of differentially tagged MUF1 constructs","journal":"Journal of molecular biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP experiment, single lab","pmids":["22709582"],"is_preprint":false},{"year":2025,"finding":"LRRC41 coimmunoprecipitates with CUL5 in bone marrow cells, supporting formation of a CRL5-LRRC41 complex; LRRC41 and STAT5 accumulate in Cul5-knockout HSCs during IL-3 stimulation, indicating CUL5 regulates LRRC41 and STAT5 levels downstream of IL-3 signaling.","method":"Co-immunoprecipitation (reciprocal), conditional knockout mouse model (Cul5Vav-Cre), proteome analysis of HSPCs","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and KO mouse model with proteomic readout, single lab","pmids":["40569692"],"is_preprint":false},{"year":2025,"finding":"CRL2LRRC41 ubiquitinates DDX5 in human spermatogonial stem cell-like cells; this ubiquitination promotes DDX5 interaction with RNA-binding protein ELAVL1 without targeting DDX5 for proteasomal degradation, thereby stabilizing Noggin (NOG) mRNA and supporting SSCLC proliferation and migration.","method":"Gene knockdown, proteomics substrate identification, co-immunoprecipitation, ubiquitination assay, functional proliferation/migration assays","journal":"BMC biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal biochemical methods (Co-IP, ubiquitination assay, proteomics) plus functional assays, single lab","pmids":["40775760"],"is_preprint":false},{"year":2026,"finding":"USP7 stabilizes LRRC41 by deubiquitination; LRRC41 activates the NF-κB pathway by targeting HNRNPC via K63-linked ubiquitination in hepatocellular carcinoma cells, constituting a USP7/LRRC41/HNRNPC/NF-κB signaling axis.","method":"IP-MS, co-immunoprecipitation, ubiquitination assays, in vitro functional assays (CCK-8, Transwell, colony formation), in vivo xenograft models","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-MS plus Co-IP plus ubiquitination assays with functional validation in vitro and in vivo, single lab","pmids":["41942610"],"is_preprint":false}],"current_model":"LRRC41 (MUF1) is a leucine-rich repeat, BC-box-containing protein that functions as a substrate-recognition subunit in at least two distinct Cullin-RING E3 ubiquitin ligase complexes: it assembles with Elongin BC, Cul5, and Rbx1 to form a CRL5 ligase, and is itself a substrate of a RhoBTB3-Cul3 ligase complex that targets it for proteasomal degradation; as the substrate receptor of CRL2LRRC41, it ubiquitinates DDX5 (promoting ELAVL1 binding and NOG mRNA stabilization) and HNRNPC (via K63-linkage, activating NF-κB), while its own stability is maintained by the deubiquitinase USP7."},"narrative":{"mechanistic_narrative":"LRRC41 (MUF1) is a leucine-rich repeat, BC-box-containing protein that functions as a substrate-recognition subunit of Cullin-RING E3 ubiquitin ligase complexes [PMID:11384984]. It assembles with Elongin BC, Cul5, and Rbx1 to reconstitute ubiquitin ligase activity in vitro [PMID:11384984], and coimmunoprecipitates with CUL5 in bone marrow cells, where CUL5 controls LRRC41 protein levels downstream of IL-3 signaling [PMID:40569692]. As the substrate receptor of a CRL2-type ligase, LRRC41 ubiquitinates DDX5 in a non-degradative manner that promotes DDX5 binding to ELAVL1 and stabilizes Noggin (NOG) mRNA, supporting spermatogonial stem cell-like proliferation and migration [PMID:40775760], and it ubiquitinates HNRNPC via K63 linkage to activate the NF-κB pathway in hepatocellular carcinoma cells [PMID:41942610]. LRRC41 is itself a regulated substrate: it is degraded by the proteasome through the RhoBTB3-Cul3 ligase complex, being the first identified substrate of RhoBTB-Cul3 ligases [PMID:22709582], while the deubiquitinase USP7 opposes this turnover and stabilizes LRRC41 [PMID:41942610]. The protein is predominantly nuclear and capable of homodimerization, relocating partially to the cytoplasm upon coexpression with RhoBTB proteins [PMID:22709582].","teleology":[{"year":2001,"claim":"Established LRRC41/MUF1 as an active E3 ligase component rather than an uncharacterized LRR protein, defining its core biochemical role as a substrate-recognition subunit of a Cul5-based ligase.","evidence":"Protein purification from rat liver with in vitro reconstitution of ubiquitin ligase activity and BC-box motif identification","pmids":["11384984"],"confidence":"High","gaps":["No physiological substrate identified at this stage","Cellular context and regulation of the ligase unknown"]},{"year":2012,"claim":"Showed that LRRC41 is itself a target of ubiquitin-mediated turnover, identifying RhoBTB3-Cul3 as the responsible ligase and placing LRRC41 within a regulatory feedback of the ubiquitin system.","evidence":"Yeast two-hybrid, reciprocal Co-IP, localization imaging, proteasome inhibitor and dominant-negative Cul3 stability assays","pmids":["22709582"],"confidence":"Medium","gaps":["Functional consequence of RhoBTB-driven degradation on CRL5 activity not resolved","Homodimerization rests on a single Co-IP","Mechanism of cytoplasmic relocation upon RhoBTB coexpression unclear"]},{"year":2025,"claim":"Connected LRRC41-CUL5 assembly to physiological signaling by showing CUL5 regulates LRRC41 (and STAT5) levels in hematopoietic stem cells downstream of IL-3.","evidence":"Reciprocal Co-IP in bone marrow cells, Cul5 conditional knockout mouse, HSPC proteomics","pmids":["40569692"],"confidence":"Medium","gaps":["Direct ubiquitination substrate within this axis not defined","Whether LRRC41 acts as receptor or passive substrate here unclear"]},{"year":2025,"claim":"Identified the first direct substrate of CRL2-LRRC41 (DDX5) and a non-degradative ubiquitination outcome linking the ligase to RNA-binding-protein function and mRNA stability.","evidence":"Knockdown, proteomic substrate ID, Co-IP, ubiquitination and proliferation/migration assays in spermatogonial stem cell-like cells","pmids":["40775760"],"confidence":"Medium","gaps":["Ubiquitin linkage type on DDX5 not defined","Whether CRL2 versus CRL5 scaffold is used not reconciled with earlier Cul5 evidence","Single cell-type context"]},{"year":2026,"claim":"Defined a stabilization-then-signaling axis in which USP7 deubiquitinates LRRC41 and LRRC41 in turn drives K63-linked ubiquitination of HNRNPC to activate NF-κB.","evidence":"IP-MS, Co-IP, ubiquitination assays, in vitro functional assays and xenograft models in hepatocellular carcinoma","pmids":["41942610"],"confidence":"Medium","gaps":["Mechanism by which K63-ubiquitinated HNRNPC activates NF-κB not detailed","Generality beyond hepatocellular carcinoma untested"]},{"year":null,"claim":"How LRRC41 partitions between CRL5 and CRL2 scaffolds and what determines its choice of degradative versus non-degradative ubiquitination across substrates remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of substrate engagement","Cullin scaffold selection rules unknown","Full substrate repertoire uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,5,6]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,2,5,6]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6]}],"complexes":["CRL5 (Elongin BC-Cul5-Rbx1)","CRL2-LRRC41","RhoBTB3-Cul3 ligase"],"partners":["CUL5","RBX1","RHOBTB1","RHOBTB2","RHOBTB3","DDX5","HNRNPC","USP7"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15345","full_name":"Leucine-rich repeat-containing protein 41","aliases":["Protein Muf1"],"length_aa":812,"mass_kda":88.7,"function":"Probable substrate recognition component of an ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q15345/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LRRC41","classification":"Not Classified","n_dependent_lines":9,"n_total_lines":1208,"dependency_fraction":0.0074503311258278145},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/LRRC41","total_profiled":1310},"omim":[{"mim_id":"618753","title":"LEUCINE-RICH REPEAT-CONTAINING PROTEIN 41; LRRC41","url":"https://www.omim.org/entry/618753"},{"mim_id":"614999","title":"CYTOCHROME P450, FAMILY 4, SUBFAMILY X, POLYPEPTIDE 1; CYP4X1","url":"https://www.omim.org/entry/614999"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nuclear bodies","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/LRRC41"},"hgnc":{"alias_symbol":["MUF1"],"prev_symbol":[]},"alphafold":{"accession":"Q15345","domains":[{"cath_id":"3.80.10.10","chopping":"647-812","consensus_level":"medium","plddt":86.4173,"start":647,"end":812}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15345","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15345-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15345-F1-predicted_aligned_error_v6.png","plddt_mean":70.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LRRC41","jax_strain_url":"https://www.jax.org/strain/search?query=LRRC41"},"sequence":{"accession":"Q15345","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15345.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15345/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15345"}},"corpus_meta":[{"pmid":"11384984","id":"PMC_11384984","title":"Muf1, a novel Elongin BC-interacting leucine-rich repeat protein that can assemble with Cul5 and Rbx1 to reconstitute a ubiquitin ligase.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11384984","citation_count":138,"is_preprint":false},{"pmid":"15485928","id":"PMC_15485928","title":"Both BC-box motifs of adenovirus protein E4orf6 are required to efficiently assemble an E3 ligase complex that degrades p53.","date":"2004","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15485928","citation_count":89,"is_preprint":false},{"pmid":"22709582","id":"PMC_22709582","title":"MUF1/leucine-rich repeat containing 41 (LRRC41), a substrate of RhoBTB-dependent cullin 3 ubiquitin ligase complexes, is a predominantly nuclear dimeric protein.","date":"2012","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/22709582","citation_count":19,"is_preprint":false},{"pmid":"8821135","id":"PMC_8821135","title":"Nifedipine-sensitive intramembrane charge movement in Purkinje cells from mouse cerebellum.","date":"1996","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/8821135","citation_count":10,"is_preprint":false},{"pmid":"37316926","id":"PMC_37316926","title":"LncRNA5251 inhibits spermatogenesis via modification of cell-cell junctions.","date":"2023","source":"Biology direct","url":"https://pubmed.ncbi.nlm.nih.gov/37316926","citation_count":8,"is_preprint":false},{"pmid":"40569692","id":"PMC_40569692","title":"The E3 ubiquitin ligase Cul5 regulates hematopoietic stem cell function for steady-state hematopoiesis in mice.","date":"2025","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/40569692","citation_count":5,"is_preprint":false},{"pmid":"36116016","id":"PMC_36116016","title":"LncRNA8276 primes cell-cell adhesion for regulation of spermatogenesis.","date":"2022","source":"Andrology","url":"https://pubmed.ncbi.nlm.nih.gov/36116016","citation_count":4,"is_preprint":false},{"pmid":"38192337","id":"PMC_38192337","title":"Targeting LRRC41 as a potential therapeutic approach for hepatocellular carcinoma.","date":"2023","source":"Frontiers in molecular biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/38192337","citation_count":2,"is_preprint":false},{"pmid":"40775760","id":"PMC_40775760","title":"CRL2LRRC41-Mediated DDX5 Ubiquitination Enhances Interaction with ELAVL1 Preventing NOG mRNA Degradation and Sustaining Proliferation and Migration of Human Spermatogonial Stem Cell-Like Cell Line.","date":"2025","source":"BMC biology","url":"https://pubmed.ncbi.nlm.nih.gov/40775760","citation_count":0,"is_preprint":false},{"pmid":"41942610","id":"PMC_41942610","title":"Suppression of LRRC41-mediated oncogenicity in hepatocellular carcinoma via USP7-targeted small molecule inhibitors.","date":"2026","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/41942610","citation_count":0,"is_preprint":false},{"pmid":"41300918","id":"PMC_41300918","title":"Decoding Multi-Omics Signatures in Lower-Grade Glioma Using Protein-Protein Interaction-Informed Graph Attention Networks and Ensemble Learning.","date":"2025","source":"Diagnostics (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/41300918","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8508,"output_tokens":1743,"usd":0.025834,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8515,"output_tokens":2369,"usd":0.0509,"stage2_stop_reason":"end_turn"},"total_usd":0.076734,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"MUF1 (LRRC41) was purified from rat liver as a novel leucine-rich repeat-containing BC-box protein that interacts with Elongin BC and assembles with Cul5 and Rbx1 to reconstitute ubiquitin ligase activity in vitro.\",\n      \"method\": \"Protein purification from rat liver, in vitro reconstitution of ubiquitin ligase activity, BC-box motif identification\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of E3 ubiquitin ligase activity with purified components, biochemical purification from native tissue\",\n      \"pmids\": [\"11384984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MUF1/LRRC41 is a predominantly nuclear, ubiquitously expressed dimeric protein that interacts with all three mammalian RhoBTB proteins (RhoBTB1, 2, 3) via immunoprecipitation; upon coexpression with RhoBTB, MUF1 partially relocates to the cytoplasm where both proteins colocalize.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, subcellular localization imaging\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and localization imaging, single lab, two orthogonal methods\",\n      \"pmids\": [\"22709582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MUF1/LRRC41 is degraded by the proteasome via a Cul5-independent mechanism mediated by the RhoBTB3-Cul3 ubiquitin ligase complex, making MUF1 the first identified substrate of RhoBTB-Cul3 ubiquitin ligase complexes.\",\n      \"method\": \"Protein stability assay, proteasome inhibitor treatment, dominant-negative Cul3 expression\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — protein stability assay with mechanistic follow-up, single lab, multiple complementary approaches\",\n      \"pmids\": [\"22709582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MUF1/LRRC41 is capable of homodimerization, consistent with other leucine-rich repeat-containing proteins.\",\n      \"method\": \"Co-immunoprecipitation of differentially tagged MUF1 constructs\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP experiment, single lab\",\n      \"pmids\": [\"22709582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LRRC41 coimmunoprecipitates with CUL5 in bone marrow cells, supporting formation of a CRL5-LRRC41 complex; LRRC41 and STAT5 accumulate in Cul5-knockout HSCs during IL-3 stimulation, indicating CUL5 regulates LRRC41 and STAT5 levels downstream of IL-3 signaling.\",\n      \"method\": \"Co-immunoprecipitation (reciprocal), conditional knockout mouse model (Cul5Vav-Cre), proteome analysis of HSPCs\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and KO mouse model with proteomic readout, single lab\",\n      \"pmids\": [\"40569692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CRL2LRRC41 ubiquitinates DDX5 in human spermatogonial stem cell-like cells; this ubiquitination promotes DDX5 interaction with RNA-binding protein ELAVL1 without targeting DDX5 for proteasomal degradation, thereby stabilizing Noggin (NOG) mRNA and supporting SSCLC proliferation and migration.\",\n      \"method\": \"Gene knockdown, proteomics substrate identification, co-immunoprecipitation, ubiquitination assay, functional proliferation/migration assays\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal biochemical methods (Co-IP, ubiquitination assay, proteomics) plus functional assays, single lab\",\n      \"pmids\": [\"40775760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"USP7 stabilizes LRRC41 by deubiquitination; LRRC41 activates the NF-κB pathway by targeting HNRNPC via K63-linked ubiquitination in hepatocellular carcinoma cells, constituting a USP7/LRRC41/HNRNPC/NF-κB signaling axis.\",\n      \"method\": \"IP-MS, co-immunoprecipitation, ubiquitination assays, in vitro functional assays (CCK-8, Transwell, colony formation), in vivo xenograft models\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-MS plus Co-IP plus ubiquitination assays with functional validation in vitro and in vivo, single lab\",\n      \"pmids\": [\"41942610\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LRRC41 (MUF1) is a leucine-rich repeat, BC-box-containing protein that functions as a substrate-recognition subunit in at least two distinct Cullin-RING E3 ubiquitin ligase complexes: it assembles with Elongin BC, Cul5, and Rbx1 to form a CRL5 ligase, and is itself a substrate of a RhoBTB3-Cul3 ligase complex that targets it for proteasomal degradation; as the substrate receptor of CRL2LRRC41, it ubiquitinates DDX5 (promoting ELAVL1 binding and NOG mRNA stabilization) and HNRNPC (via K63-linkage, activating NF-κB), while its own stability is maintained by the deubiquitinase USP7.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LRRC41 (MUF1) is a leucine-rich repeat, BC-box-containing protein that functions as a substrate-recognition subunit of Cullin-RING E3 ubiquitin ligase complexes [#0]. It assembles with Elongin BC, Cul5, and Rbx1 to reconstitute ubiquitin ligase activity in vitro [#0], and coimmunoprecipitates with CUL5 in bone marrow cells, where CUL5 controls LRRC41 protein levels downstream of IL-3 signaling [#4]. As the substrate receptor of a CRL2-type ligase, LRRC41 ubiquitinates DDX5 in a non-degradative manner that promotes DDX5 binding to ELAVL1 and stabilizes Noggin (NOG) mRNA, supporting spermatogonial stem cell-like proliferation and migration [#5], and it ubiquitinates HNRNPC via K63 linkage to activate the NF-\\u03baB pathway in hepatocellular carcinoma cells [#6]. LRRC41 is itself a regulated substrate: it is degraded by the proteasome through the RhoBTB3-Cul3 ligase complex, being the first identified substrate of RhoBTB-Cul3 ligases [#1, #2], while the deubiquitinase USP7 opposes this turnover and stabilizes LRRC41 [#6]. The protein is predominantly nuclear and capable of homodimerization, relocating partially to the cytoplasm upon coexpression with RhoBTB proteins [#1].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established LRRC41/MUF1 as an active E3 ligase component rather than an uncharacterized LRR protein, defining its core biochemical role as a substrate-recognition subunit of a Cul5-based ligase.\",\n      \"evidence\": \"Protein purification from rat liver with in vitro reconstitution of ubiquitin ligase activity and BC-box motif identification\",\n      \"pmids\": [\"11384984\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No physiological substrate identified at this stage\", \"Cellular context and regulation of the ligase unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed that LRRC41 is itself a target of ubiquitin-mediated turnover, identifying RhoBTB3-Cul3 as the responsible ligase and placing LRRC41 within a regulatory feedback of the ubiquitin system.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal Co-IP, localization imaging, proteasome inhibitor and dominant-negative Cul3 stability assays\",\n      \"pmids\": [\"22709582\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of RhoBTB-driven degradation on CRL5 activity not resolved\", \"Homodimerization rests on a single Co-IP\", \"Mechanism of cytoplasmic relocation upon RhoBTB coexpression unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected LRRC41-CUL5 assembly to physiological signaling by showing CUL5 regulates LRRC41 (and STAT5) levels in hematopoietic stem cells downstream of IL-3.\",\n      \"evidence\": \"Reciprocal Co-IP in bone marrow cells, Cul5 conditional knockout mouse, HSPC proteomics\",\n      \"pmids\": [\"40569692\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ubiquitination substrate within this axis not defined\", \"Whether LRRC41 acts as receptor or passive substrate here unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified the first direct substrate of CRL2-LRRC41 (DDX5) and a non-degradative ubiquitination outcome linking the ligase to RNA-binding-protein function and mRNA stability.\",\n      \"evidence\": \"Knockdown, proteomic substrate ID, Co-IP, ubiquitination and proliferation/migration assays in spermatogonial stem cell-like cells\",\n      \"pmids\": [\"40775760\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin linkage type on DDX5 not defined\", \"Whether CRL2 versus CRL5 scaffold is used not reconciled with earlier Cul5 evidence\", \"Single cell-type context\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined a stabilization-then-signaling axis in which USP7 deubiquitinates LRRC41 and LRRC41 in turn drives K63-linked ubiquitination of HNRNPC to activate NF-\\u03baB.\",\n      \"evidence\": \"IP-MS, Co-IP, ubiquitination assays, in vitro functional assays and xenograft models in hepatocellular carcinoma\",\n      \"pmids\": [\"41942610\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which K63-ubiquitinated HNRNPC activates NF-\\u03baB not detailed\", \"Generality beyond hepatocellular carcinoma untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How LRRC41 partitions between CRL5 and CRL2 scaffolds and what determines its choice of degradative versus non-degradative ubiquitination across substrates remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of substrate engagement\", \"Cullin scaffold selection rules unknown\", \"Full substrate repertoire uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 5, 6]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 2, 5, 6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"complexes\": [\"CRL5 (Elongin BC-Cul5-Rbx1)\", \"CRL2-LRRC41\", \"RhoBTB3-Cul3 ligase\"],\n    \"partners\": [\"CUL5\", \"RBX1\", \"RhoBTB1\", \"RhoBTB2\", \"RhoBTB3\", \"DDX5\", \"HNRNPC\", \"USP7\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}