{"gene":"RNF182","run_date":"2026-06-10T06:43:37","timeline":{"discoveries":[{"year":2008,"finding":"RNF182 is a brain-enriched cytoplasmic RING finger protein with E3 ubiquitin ligase activity; it stimulates E2-dependent polyubiquitination in vitro and targets ATP6V0C for degradation via the ubiquitin-proteasome pathway, as established by yeast two-hybrid screening, co-precipitation, and overexpression experiments.","method":"In vitro ubiquitination assay, yeast two-hybrid, co-immunoprecipitation, overexpression with protein degradation assay","journal":"Molecular neurodegeneration","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro E3 ligase activity demonstrated, substrate (ATP6V0C) identified by yeast two-hybrid and confirmed by co-precipitation and degradation assay in a single study with multiple orthogonal methods","pmids":["18298843"],"is_preprint":false},{"year":2022,"finding":"PCDHB14 promotes RNF182-mediated K48-linked ubiquitination and proteasomal degradation of p65 (NF-κB subunit), thereby blocking p65 binding to the SLC7A11 promoter and reducing SLC7A11 expression to induce ferroptosis in hepatocellular carcinoma cells.","method":"Co-immunoprecipitation, Western blot (ubiquitination assay), chromatin immunoprecipitation, reporter assay, loss-of-function and overexpression experiments","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and functional rescue experiments in a single lab with multiple orthogonal methods (ubiquitination assay, ChIP, reporter), but no in vitro reconstitution with purified proteins","pmids":["35688944"],"is_preprint":false},{"year":2023,"finding":"RNF182 promotes ubiquitination and degradation of p65, thereby suppressing p65-driven transcription of PDL1, reducing immune evasion in lung adenocarcinoma; co-immunoprecipitation confirmed direct RNF182–p65 interaction.","method":"Co-immunoprecipitation, Western blot (ubiquitination), ChIP-qPCR, luciferase reporter assay, CD8+ T cell co-culture cytotoxicity assay, in vivo xenograft","journal":"Immunity, inflammation and disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single lab with multiple orthogonal methods (Co-IP, ubiquitination WB, ChIP, reporter, in vivo), consistent with findings in PMID 35688944","pmids":["37249301"],"is_preprint":false},{"year":2022,"finding":"Friedelin (FR) recruits RNF182 to increase K48-linked ubiquitination of p65 and promotes p62-mediated autophagic degradation of p65, thereby inhibiting NF-κB pathway activation in tenocytes; blocking ubiquitination reversed p65 degradation by FR.","method":"Co-immunoprecipitation, ubiquitination assay (K48-linkage-specific), autophagy flux assay, pharmacological inhibitor rescue, in vivo tendinopathy mouse model","journal":"Nutrients","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single lab, multiple orthogonal methods (Co-IP, K48-ubiquitin WB, rescue with ubiquitination blocker, in vivo model), but not independently replicated","pmids":["35458235"],"is_preprint":false},{"year":2026,"finding":"Friedelin enhances RNF182-p65 association, facilitating autophagic degradation of p65 via selective inhibition of p65 phosphorylation (independent of IKK activity) to suppress NF-κB signalling and reduce inflammation in nucleus pulposus cells and intervertebral disc degeneration models.","method":"Co-immunoprecipitation, Western blot, in vivo cervical spine instability mouse model, in vitro NP cell assays","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single lab, Co-IP plus in vivo and in vitro functional validation, consistent with PMID 35458235 but not independently replicated","pmids":["41503854"],"is_preprint":false},{"year":2025,"finding":"RNF182 mediates ubiquitination and degradation of MFN2 (Mitofusin-2), leading to mitochondrial dysfunction; TGF-β1 induces RNF182 expression and inhibition of RNF182 by rhIL-1Ra stabilizes MFN2, preserves mitochondrial respiration and ATP production, and attenuates renal fibrosis.","method":"In vitro ubiquitination/degradation assay, rescue experiments (RNF182 inhibition), in vivo UUO and 5/6Nx mouse models, Western blot","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single lab, RNF182-MFN2 axis confirmed by rescue experiments in vitro and in vivo with two orthogonal disease models, novel substrate identification","pmids":["41461638"],"is_preprint":false},{"year":2018,"finding":"Silencing RNF182 in a rat myocardial ischemia-reperfusion injury model activates the mTOR signaling pathway (upregulates mTOR, S6K1, eEF2, Bcl-2) and reduces cardiomyocyte apoptosis and ventricular remodeling; the mTOR inhibitor PITE reversed these protective effects, placing RNF182 upstream of mTOR as a negative regulator.","method":"shRNA knockdown in rat MIRI model, pharmacological rescue with mTOR inhibitor, Western blot, echocardiography, apoptosis assays","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic epistasis (KD + pathway inhibitor rescue) in a single in vivo model; pathway placement supported but mechanistic details limited to gene expression measurements","pmids":["30450663"],"is_preprint":false},{"year":2025,"finding":"Fish (grass carp) RNF182 ortholog (CiE3RNF182) directly interacts with RIG-I and induces Lys-33-linked ubiquitination at the Lys33 residue of RIG-I, triggering RIG-I degradation and inhibiting downstream antiviral type I IFN signaling; CRISPR/Cas9-mediated deletion of E3RNF182 in rare minnow enhanced survival after GCRV infection.","method":"Co-immunoprecipitation, linkage-specific ubiquitination assay (K33), CRISPR/Cas9 knockout, viral infection survival assay, cellular localization analysis","journal":"Fish & shellfish immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — K33-specific ubiquitination and RIG-I degradation shown by Co-IP and ubiquitination assay; functional consequence validated by CRISPR KO in vivo; fish ortholog, not mammalian, slightly reduces generalizability","pmids":["40049566"],"is_preprint":false},{"year":2026,"finding":"siRNA-mediated silencing of RNF182 in U87MG glioblastoma cells significantly reduced cell proliferation, establishing a functional role for RNF182 in promoting glioblastoma cell growth.","method":"siRNA knockdown, proliferation assay (cell counting), RT-qPCR, Western blot","journal":"Cancers","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method (siRNA + proliferation assay), no mechanistic pathway placement beyond loss-of-function phenotype","pmids":["42073544"],"is_preprint":false},{"year":2010,"finding":"RNF182 is a target gene regulated by MeCP2 in neurons; chromatin immunoprecipitation confirmed MeCP2 binding to the methylated CpG island of RNF182, and expression profiling showed RNF182 is upregulated in cells expressing mutant MeCP2, implicating it in MeCP2-controlled cell survival/apoptosis pathways in Rett syndrome.","method":"Microarray gene expression profiling, RT-qPCR, chromatin immunoprecipitation (ChIP), bisulfite sequencing","journal":"Journal of cellular and molecular medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — ChIP confirms MeCP2 binding to RNF182 locus in a single study; functional link to apoptosis is inferred, not directly demonstrated","pmids":["20569274"],"is_preprint":false}],"current_model":"RNF182 is a brain-enriched (but more broadly expressed) RING-domain E3 ubiquitin ligase that catalyzes polyubiquitination of multiple substrates—including ATP6V0C (targeting it for proteasomal degradation), p65/RelA (K48-linked ubiquitination leading to proteasomal or autophagic degradation and consequent suppression of NF-κB/PDL1 signaling), MFN2 (ubiquitination leading to mitochondrial dysfunction in renal fibrosis), and, in fish orthologs, RIG-I (K33-linked ubiquitination triggering RIG-I degradation and suppression of antiviral innate immunity); its activity is upregulated by inflammatory stimuli and in neurodegenerative and oncological contexts, and is repressed by promoter hypermethylation in several cancers."},"narrative":{"mechanistic_narrative":"RNF182 is a brain-enriched cytoplasmic RING-domain E3 ubiquitin ligase that stimulates E2-dependent polyubiquitination and directs selected substrates for degradation, thereby tuning inflammatory, mitochondrial, and survival signaling [PMID:18298843]. Its first-identified substrate, ATP6V0C, is targeted for proteasomal degradation [PMID:18298843]. A recurrent theme across tissue contexts is the negative regulation of NF-κB: RNF182 binds the p65/RelA subunit and catalyzes K48-linked ubiquitination that drives p65 degradation, depleting p65 from target promoters — reducing SLC7A11 expression to promote ferroptosis in hepatocellular carcinoma [PMID:35688944] and suppressing PDL1 transcription to limit immune evasion in lung adenocarcinoma [PMID:37249301]. The same RNF182–p65 axis can route p65 to p62-mediated autophagic degradation, an activity engaged pharmacologically by friedelin to dampen NF-κB-driven inflammation [PMID:35458235, PMID:41503854]. Beyond p65, RNF182 ubiquitinates MFN2, causing mitochondrial dysfunction in renal fibrosis [PMID:41461638], and in the grass carp ortholog it attaches K33-linked chains to RIG-I to trigger its degradation and suppress antiviral type I IFN signaling [PMID:40049566]. Functionally, RNF182 acts upstream of mTOR as a negative regulator in myocardial ischemia-reperfusion injury [PMID:30450663] and supports glioblastoma cell proliferation [PMID:42073544].","teleology":[{"year":2008,"claim":"Established RNF182 as a bona fide E3 ubiquitin ligase and identified its first degradation substrate, answering whether the protein had catalytic ubiquitination activity and what it acted upon.","evidence":"In vitro ubiquitination assay, yeast two-hybrid, co-IP, and degradation assay in brain-derived context","pmids":["18298843"],"confidence":"High","gaps":["Physiological consequences of ATP6V0C turnover not defined","E2 partner specificity in cells not resolved","No structural basis for substrate selection"]},{"year":2010,"claim":"Placed RNF182 transcription under MeCP2 control, raising the possibility that its expression is epigenetically regulated in a neuronal survival context.","evidence":"Microarray, RT-qPCR, ChIP, and bisulfite sequencing in MeCP2-mutant neuronal cells","pmids":["20569274"],"confidence":"Low","gaps":["Functional link to apoptosis inferred, not directly demonstrated","Direction of regulation across cell types unclear","No connection to RNF182 ligase activity established"]},{"year":2018,"claim":"Positioned RNF182 as a negative upstream regulator of mTOR signaling in cardiac injury, linking it to apoptosis and remodeling control.","evidence":"shRNA knockdown plus mTOR-inhibitor rescue in a rat myocardial ischemia-reperfusion model","pmids":["30450663"],"confidence":"Medium","gaps":["Direct substrate connecting RNF182 to mTOR not identified","Epistasis based on expression markers, not biochemistry","Mammalian-cell mechanism not reconstituted"]},{"year":2022,"claim":"Defined p65/RelA as a key RNF182 substrate, showing K48-linked ubiquitination and degradation that lowers SLC7A11 to drive ferroptosis, and that a partner (PCDHB14) promotes this activity.","evidence":"Reciprocal Co-IP, K48 ubiquitination WB, ChIP, and reporter assays in hepatocellular carcinoma cells","pmids":["35688944"],"confidence":"Medium","gaps":["No in vitro reconstitution with purified proteins","Direct vs. PCDHB14-dependent ubiquitination not separated","Single-lab finding"]},{"year":2022,"claim":"Extended the RNF182–p65 axis to an autophagic degradation route engaged by friedelin, showing p62-mediated clearance of p65 suppresses NF-κB-driven inflammation.","evidence":"Co-IP, K48-linkage ubiquitination assay, autophagy flux, inhibitor rescue, and in vivo tendinopathy model","pmids":["35458235"],"confidence":"Medium","gaps":["Switch between proteasomal and autophagic fate of p65 unexplained","Mechanism of friedelin-induced RNF182 recruitment unknown","Not independently replicated"]},{"year":2023,"claim":"Generalized RNF182-mediated p65 degradation to immune evasion, showing suppression of PDL1 transcription and restored CD8+ T cell cytotoxicity in lung adenocarcinoma.","evidence":"Co-IP, ubiquitination WB, ChIP-qPCR, reporter assay, T-cell co-culture, and xenograft","pmids":["37249301"],"confidence":"Medium","gaps":["Direct ubiquitination of p65 not reconstituted","Determinants of RNF182 abundance in tumors not defined","Single-lab finding"]},{"year":2025,"claim":"Identified MFN2 as a new RNF182 substrate, connecting its ligase activity to mitochondrial dysfunction and renal fibrosis under TGF-β1 induction.","evidence":"In vitro ubiquitination/degradation, RNF182-inhibition rescue, and UUO plus 5/6Nx in vivo models","pmids":["41461638"],"confidence":"Medium","gaps":["Ubiquitin linkage type on MFN2 not specified","Substrate selectivity vs. p65 not addressed","Single-lab finding"]},{"year":2025,"claim":"Showed an evolutionarily conserved immune role for the fish ortholog, with K33-linked ubiquitination of RIG-I driving its degradation and dampening antiviral IFN responses.","evidence":"Co-IP, K33-linkage ubiquitination assay, and CRISPR/Cas9 knockout with viral survival assay in grass carp/rare minnow","pmids":["40049566"],"confidence":"Medium","gaps":["Mammalian RIG-I regulation by RNF182 not tested","Generalizability of K33 linkage to other substrates unknown","Fish ortholog limits direct extrapolation"]},{"year":2026,"claim":"Confirmed a pro-proliferative role for RNF182 in glioblastoma, though without mechanistic pathway placement.","evidence":"siRNA knockdown with proliferation assay, RT-qPCR, and Western blot in U87MG cells","pmids":["42073544"],"confidence":"Low","gaps":["Single method (loss-of-function phenotype) without substrate link","No reconciliation with tumor-suppressive p65-degradation role","Pathway not defined"]},{"year":null,"claim":"How RNF182 selects among its diverse substrates (ATP6V0C, p65, MFN2, RIG-I) and chooses ubiquitin linkage type (K48 vs K33) and degradation route (proteasomal vs autophagic) remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of substrate recognition","No purified-protein reconstitution defining linkage specificity","Context-dependent oncogenic vs tumor-suppressive roles unreconciled"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,2,3,5,7]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2,5,7]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2,3,4]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,2,5]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,7]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[1,6]}],"complexes":[],"partners":["RELA","ATP6V0C","MFN2","PCDHB14","RIGI"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8N6D2","full_name":"E3 ubiquitin-protein ligase RNF182","aliases":["RING finger protein 182","RING-type E3 ubiquitin transferase RNF182"],"length_aa":247,"mass_kda":27.4,"function":"E3 ubiquitin-protein ligase that mediates the ubiquitination of ATP6V0C and targets it to degradation via the ubiquitin-proteasome pathway (PubMed:18298843). Also plays a role in the inhibition of TLR-triggered innate immune response by mediating 'Lys'-48-linked ubiquitination and subsequent degradation of NF-kappa-B component RELA (PubMed:31432514)","subcellular_location":"Membrane; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q8N6D2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RNF182","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/RNF182","total_profiled":1310},"omim":[{"mim_id":"621029","title":"RING FINGER PROTEIN 183; RNF183","url":"https://www.omim.org/entry/621029"},{"mim_id":"621026","title":"RING FINGER PROTEIN 182; RNF182","url":"https://www.omim.org/entry/621026"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":8.0},{"tissue":"brain","ntpm":15.9},{"tissue":"retina","ntpm":8.1}],"url":"https://www.proteinatlas.org/search/RNF182"},"hgnc":{"alias_symbol":["MGC33993"],"prev_symbol":[]},"alphafold":{"accession":"Q8N6D2","domains":[{"cath_id":"3.30.40.10","chopping":"14-95","consensus_level":"high","plddt":86.7856,"start":14,"end":95},{"cath_id":"4.10.860","chopping":"176-242","consensus_level":"high","plddt":84.7707,"start":176,"end":242}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N6D2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N6D2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N6D2-F1-predicted_aligned_error_v6.png","plddt_mean":70.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RNF182","jax_strain_url":"https://www.jax.org/strain/search?query=RNF182"},"sequence":{"accession":"Q8N6D2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8N6D2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8N6D2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N6D2"}},"corpus_meta":[{"pmid":"35688944","id":"PMC_35688944","title":"PCDHB14 promotes ferroptosis and is a novel tumor suppressor in hepatocellular carcinoma.","date":"2022","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/35688944","citation_count":54,"is_preprint":false},{"pmid":"18298843","id":"PMC_18298843","title":"A novel brain-enriched E3 ubiquitin ligase RNF182 is up regulated in the brains of Alzheimer's patients and targets ATP6V0C for degradation.","date":"2008","source":"Molecular neurodegeneration","url":"https://pubmed.ncbi.nlm.nih.gov/18298843","citation_count":53,"is_preprint":false},{"pmid":"32486221","id":"PMC_32486221","title":"The Role of Tissue-Specific Ubiquitin Ligases, RNF183, RNF186, RNF182 and RNF152, in Disease and Biological Function.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32486221","citation_count":49,"is_preprint":false},{"pmid":"37783761","id":"PMC_37783761","title":"Identifying potential biomarkers of idiopathic pulmonary fibrosis through machine learning analysis.","date":"2023","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/37783761","citation_count":40,"is_preprint":false},{"pmid":"20569274","id":"PMC_20569274","title":"Cell cloning-based transcriptome analysis in Rett patients: relevance to the pathogenesis of Rett syndrome of new human MeCP2 target genes.","date":"2010","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/20569274","citation_count":27,"is_preprint":false},{"pmid":"24475022","id":"PMC_24475022","title":"An integrative CGH, MSI and candidate genes methylation analysis of colorectal tumors.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24475022","citation_count":26,"is_preprint":false},{"pmid":"35458235","id":"PMC_35458235","title":"Friedelin Alleviates the Pathogenesis of Collagenase-Induced Tendinopathy in Mice by Promoting the Selective Autophagic Degradation of p65.","date":"2022","source":"Nutrients","url":"https://pubmed.ncbi.nlm.nih.gov/35458235","citation_count":19,"is_preprint":false},{"pmid":"34652043","id":"PMC_34652043","title":"Ammonia induces autophagy via circ-IFNLR1/miR-2188-5p/RNF182 axis in tracheas of chickens.","date":"2021","source":"BioFactors (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/34652043","citation_count":16,"is_preprint":false},{"pmid":"30450663","id":"PMC_30450663","title":"Activation of the mammalian target of rapamycin signaling pathway underlies a novel inhibitory role of ring finger protein 182 in ventricular remodeling after myocardial ischemia-reperfusion injury.","date":"2018","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30450663","citation_count":11,"is_preprint":false},{"pmid":"32353685","id":"PMC_32353685","title":"Identification and verification of EOMEs regulated network in Alopecia areata.","date":"2020","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/32353685","citation_count":11,"is_preprint":false},{"pmid":"38894865","id":"PMC_38894865","title":"SIRPG promotes lung squamous cell carcinoma pathogenesis via M1 macrophages: a multi-omics study integrating data and Mendelian randomization.","date":"2024","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/38894865","citation_count":9,"is_preprint":false},{"pmid":"37249301","id":"PMC_37249301","title":"RNF182 induces p65 ubiquitination to affect PDL1 transcription and suppress immune evasion in lung adenocarcinoma.","date":"2023","source":"Immunity, inflammation and disease","url":"https://pubmed.ncbi.nlm.nih.gov/37249301","citation_count":8,"is_preprint":false},{"pmid":"36686776","id":"PMC_36686776","title":"Inhibition of RNF182 mediated by Bap promotes non-small cell lung cancer progression.","date":"2023","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36686776","citation_count":6,"is_preprint":false},{"pmid":"36862916","id":"PMC_36862916","title":"The role of ferroptosis-related genes in airway epithelial cells of asthmatic patients based on bioinformatics.","date":"2023","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36862916","citation_count":5,"is_preprint":false},{"pmid":"40049566","id":"PMC_40049566","title":"The E3 ubiquitin ligase RNF182 regulates the induction of innate immune response against GCRV by mediating the ubiquitination of RIG-I in grass carp (Ctenopharyngodon idella) and rare minnow (Gobiocypris rarus).","date":"2025","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/40049566","citation_count":1,"is_preprint":false},{"pmid":"41503854","id":"PMC_41503854","title":"Friedelin Ameliorates Nucleus Pulposus Inflammation by Increasing p65 Autophagic Degradation to Inhibit NF-κB Signalling Pathway.","date":"2026","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41503854","citation_count":1,"is_preprint":false},{"pmid":"41461638","id":"PMC_41461638","title":"IL‑1 receptor antagonism attenuates renal fibrosis via RNF182‑driven MFN2 destabilization and mitochondrial dysfunction.","date":"2025","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/41461638","citation_count":0,"is_preprint":false},{"pmid":"42073544","id":"PMC_42073544","title":"Overexpression of the Ubiquitin Ligase RNF182 Is Associated with High-Grade Gliomas.","date":"2026","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/42073544","citation_count":0,"is_preprint":false},{"pmid":"41713227","id":"PMC_41713227","title":"Identifying the strongest novel gene-respiratory disease interactions for rheumatoid arthritis risk.","date":"2026","source":"Seminars in arthritis and rheumatism","url":"https://pubmed.ncbi.nlm.nih.gov/41713227","citation_count":0,"is_preprint":false},{"pmid":"41940665","id":"PMC_41940665","title":"Diabetes affects the composition of the respiratory tract microbiome and transcriptome in patients with viral pneumonia.","date":"2026","source":"Microbiology spectrum","url":"https://pubmed.ncbi.nlm.nih.gov/41940665","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13371,"output_tokens":2726,"usd":0.040502,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9983,"output_tokens":3292,"usd":0.066107,"stage2_stop_reason":"end_turn"},"total_usd":0.106609,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"RNF182 is a brain-enriched cytoplasmic RING finger protein with E3 ubiquitin ligase activity; it stimulates E2-dependent polyubiquitination in vitro and targets ATP6V0C for degradation via the ubiquitin-proteasome pathway, as established by yeast two-hybrid screening, co-precipitation, and overexpression experiments.\",\n      \"method\": \"In vitro ubiquitination assay, yeast two-hybrid, co-immunoprecipitation, overexpression with protein degradation assay\",\n      \"journal\": \"Molecular neurodegeneration\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro E3 ligase activity demonstrated, substrate (ATP6V0C) identified by yeast two-hybrid and confirmed by co-precipitation and degradation assay in a single study with multiple orthogonal methods\",\n      \"pmids\": [\"18298843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PCDHB14 promotes RNF182-mediated K48-linked ubiquitination and proteasomal degradation of p65 (NF-κB subunit), thereby blocking p65 binding to the SLC7A11 promoter and reducing SLC7A11 expression to induce ferroptosis in hepatocellular carcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation, Western blot (ubiquitination assay), chromatin immunoprecipitation, reporter assay, loss-of-function and overexpression experiments\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and functional rescue experiments in a single lab with multiple orthogonal methods (ubiquitination assay, ChIP, reporter), but no in vitro reconstitution with purified proteins\",\n      \"pmids\": [\"35688944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RNF182 promotes ubiquitination and degradation of p65, thereby suppressing p65-driven transcription of PDL1, reducing immune evasion in lung adenocarcinoma; co-immunoprecipitation confirmed direct RNF182–p65 interaction.\",\n      \"method\": \"Co-immunoprecipitation, Western blot (ubiquitination), ChIP-qPCR, luciferase reporter assay, CD8+ T cell co-culture cytotoxicity assay, in vivo xenograft\",\n      \"journal\": \"Immunity, inflammation and disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single lab with multiple orthogonal methods (Co-IP, ubiquitination WB, ChIP, reporter, in vivo), consistent with findings in PMID 35688944\",\n      \"pmids\": [\"37249301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Friedelin (FR) recruits RNF182 to increase K48-linked ubiquitination of p65 and promotes p62-mediated autophagic degradation of p65, thereby inhibiting NF-κB pathway activation in tenocytes; blocking ubiquitination reversed p65 degradation by FR.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K48-linkage-specific), autophagy flux assay, pharmacological inhibitor rescue, in vivo tendinopathy mouse model\",\n      \"journal\": \"Nutrients\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single lab, multiple orthogonal methods (Co-IP, K48-ubiquitin WB, rescue with ubiquitination blocker, in vivo model), but not independently replicated\",\n      \"pmids\": [\"35458235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Friedelin enhances RNF182-p65 association, facilitating autophagic degradation of p65 via selective inhibition of p65 phosphorylation (independent of IKK activity) to suppress NF-κB signalling and reduce inflammation in nucleus pulposus cells and intervertebral disc degeneration models.\",\n      \"method\": \"Co-immunoprecipitation, Western blot, in vivo cervical spine instability mouse model, in vitro NP cell assays\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single lab, Co-IP plus in vivo and in vitro functional validation, consistent with PMID 35458235 but not independently replicated\",\n      \"pmids\": [\"41503854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RNF182 mediates ubiquitination and degradation of MFN2 (Mitofusin-2), leading to mitochondrial dysfunction; TGF-β1 induces RNF182 expression and inhibition of RNF182 by rhIL-1Ra stabilizes MFN2, preserves mitochondrial respiration and ATP production, and attenuates renal fibrosis.\",\n      \"method\": \"In vitro ubiquitination/degradation assay, rescue experiments (RNF182 inhibition), in vivo UUO and 5/6Nx mouse models, Western blot\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single lab, RNF182-MFN2 axis confirmed by rescue experiments in vitro and in vivo with two orthogonal disease models, novel substrate identification\",\n      \"pmids\": [\"41461638\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Silencing RNF182 in a rat myocardial ischemia-reperfusion injury model activates the mTOR signaling pathway (upregulates mTOR, S6K1, eEF2, Bcl-2) and reduces cardiomyocyte apoptosis and ventricular remodeling; the mTOR inhibitor PITE reversed these protective effects, placing RNF182 upstream of mTOR as a negative regulator.\",\n      \"method\": \"shRNA knockdown in rat MIRI model, pharmacological rescue with mTOR inhibitor, Western blot, echocardiography, apoptosis assays\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic epistasis (KD + pathway inhibitor rescue) in a single in vivo model; pathway placement supported but mechanistic details limited to gene expression measurements\",\n      \"pmids\": [\"30450663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Fish (grass carp) RNF182 ortholog (CiE3RNF182) directly interacts with RIG-I and induces Lys-33-linked ubiquitination at the Lys33 residue of RIG-I, triggering RIG-I degradation and inhibiting downstream antiviral type I IFN signaling; CRISPR/Cas9-mediated deletion of E3RNF182 in rare minnow enhanced survival after GCRV infection.\",\n      \"method\": \"Co-immunoprecipitation, linkage-specific ubiquitination assay (K33), CRISPR/Cas9 knockout, viral infection survival assay, cellular localization analysis\",\n      \"journal\": \"Fish & shellfish immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — K33-specific ubiquitination and RIG-I degradation shown by Co-IP and ubiquitination assay; functional consequence validated by CRISPR KO in vivo; fish ortholog, not mammalian, slightly reduces generalizability\",\n      \"pmids\": [\"40049566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"siRNA-mediated silencing of RNF182 in U87MG glioblastoma cells significantly reduced cell proliferation, establishing a functional role for RNF182 in promoting glioblastoma cell growth.\",\n      \"method\": \"siRNA knockdown, proliferation assay (cell counting), RT-qPCR, Western blot\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (siRNA + proliferation assay), no mechanistic pathway placement beyond loss-of-function phenotype\",\n      \"pmids\": [\"42073544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"RNF182 is a target gene regulated by MeCP2 in neurons; chromatin immunoprecipitation confirmed MeCP2 binding to the methylated CpG island of RNF182, and expression profiling showed RNF182 is upregulated in cells expressing mutant MeCP2, implicating it in MeCP2-controlled cell survival/apoptosis pathways in Rett syndrome.\",\n      \"method\": \"Microarray gene expression profiling, RT-qPCR, chromatin immunoprecipitation (ChIP), bisulfite sequencing\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — ChIP confirms MeCP2 binding to RNF182 locus in a single study; functional link to apoptosis is inferred, not directly demonstrated\",\n      \"pmids\": [\"20569274\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RNF182 is a brain-enriched (but more broadly expressed) RING-domain E3 ubiquitin ligase that catalyzes polyubiquitination of multiple substrates—including ATP6V0C (targeting it for proteasomal degradation), p65/RelA (K48-linked ubiquitination leading to proteasomal or autophagic degradation and consequent suppression of NF-κB/PDL1 signaling), MFN2 (ubiquitination leading to mitochondrial dysfunction in renal fibrosis), and, in fish orthologs, RIG-I (K33-linked ubiquitination triggering RIG-I degradation and suppression of antiviral innate immunity); its activity is upregulated by inflammatory stimuli and in neurodegenerative and oncological contexts, and is repressed by promoter hypermethylation in several cancers.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RNF182 is a brain-enriched cytoplasmic RING-domain E3 ubiquitin ligase that stimulates E2-dependent polyubiquitination and directs selected substrates for degradation, thereby tuning inflammatory, mitochondrial, and survival signaling [#0]. Its first-identified substrate, ATP6V0C, is targeted for proteasomal degradation [#0]. A recurrent theme across tissue contexts is the negative regulation of NF-\\u03baB: RNF182 binds the p65/RelA subunit and catalyzes K48-linked ubiquitination that drives p65 degradation, depleting p65 from target promoters \\u2014 reducing SLC7A11 expression to promote ferroptosis in hepatocellular carcinoma [#1] and suppressing PDL1 transcription to limit immune evasion in lung adenocarcinoma [#2]. The same RNF182\\u2013p65 axis can route p65 to p62-mediated autophagic degradation, an activity engaged pharmacologically by friedelin to dampen NF-\\u03baB-driven inflammation [#3, #4]. Beyond p65, RNF182 ubiquitinates MFN2, causing mitochondrial dysfunction in renal fibrosis [#5], and in the grass carp ortholog it attaches K33-linked chains to RIG-I to trigger its degradation and suppress antiviral type I IFN signaling [#7]. Functionally, RNF182 acts upstream of mTOR as a negative regulator in myocardial ischemia-reperfusion injury [#6] and supports glioblastoma cell proliferation [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established RNF182 as a bona fide E3 ubiquitin ligase and identified its first degradation substrate, answering whether the protein had catalytic ubiquitination activity and what it acted upon.\",\n      \"evidence\": \"In vitro ubiquitination assay, yeast two-hybrid, co-IP, and degradation assay in brain-derived context\",\n      \"pmids\": [\"18298843\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological consequences of ATP6V0C turnover not defined\", \"E2 partner specificity in cells not resolved\", \"No structural basis for substrate selection\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Placed RNF182 transcription under MeCP2 control, raising the possibility that its expression is epigenetically regulated in a neuronal survival context.\",\n      \"evidence\": \"Microarray, RT-qPCR, ChIP, and bisulfite sequencing in MeCP2-mutant neuronal cells\",\n      \"pmids\": [\"20569274\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Functional link to apoptosis inferred, not directly demonstrated\", \"Direction of regulation across cell types unclear\", \"No connection to RNF182 ligase activity established\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Positioned RNF182 as a negative upstream regulator of mTOR signaling in cardiac injury, linking it to apoptosis and remodeling control.\",\n      \"evidence\": \"shRNA knockdown plus mTOR-inhibitor rescue in a rat myocardial ischemia-reperfusion model\",\n      \"pmids\": [\"30450663\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct substrate connecting RNF182 to mTOR not identified\", \"Epistasis based on expression markers, not biochemistry\", \"Mammalian-cell mechanism not reconstituted\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined p65/RelA as a key RNF182 substrate, showing K48-linked ubiquitination and degradation that lowers SLC7A11 to drive ferroptosis, and that a partner (PCDHB14) promotes this activity.\",\n      \"evidence\": \"Reciprocal Co-IP, K48 ubiquitination WB, ChIP, and reporter assays in hepatocellular carcinoma cells\",\n      \"pmids\": [\"35688944\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro reconstitution with purified proteins\", \"Direct vs. PCDHB14-dependent ubiquitination not separated\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended the RNF182\\u2013p65 axis to an autophagic degradation route engaged by friedelin, showing p62-mediated clearance of p65 suppresses NF-\\u03baB-driven inflammation.\",\n      \"evidence\": \"Co-IP, K48-linkage ubiquitination assay, autophagy flux, inhibitor rescue, and in vivo tendinopathy model\",\n      \"pmids\": [\"35458235\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Switch between proteasomal and autophagic fate of p65 unexplained\", \"Mechanism of friedelin-induced RNF182 recruitment unknown\", \"Not independently replicated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Generalized RNF182-mediated p65 degradation to immune evasion, showing suppression of PDL1 transcription and restored CD8+ T cell cytotoxicity in lung adenocarcinoma.\",\n      \"evidence\": \"Co-IP, ubiquitination WB, ChIP-qPCR, reporter assay, T-cell co-culture, and xenograft\",\n      \"pmids\": [\"37249301\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ubiquitination of p65 not reconstituted\", \"Determinants of RNF182 abundance in tumors not defined\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified MFN2 as a new RNF182 substrate, connecting its ligase activity to mitochondrial dysfunction and renal fibrosis under TGF-\\u03b21 induction.\",\n      \"evidence\": \"In vitro ubiquitination/degradation, RNF182-inhibition rescue, and UUO plus 5/6Nx in vivo models\",\n      \"pmids\": [\"41461638\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin linkage type on MFN2 not specified\", \"Substrate selectivity vs. p65 not addressed\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed an evolutionarily conserved immune role for the fish ortholog, with K33-linked ubiquitination of RIG-I driving its degradation and dampening antiviral IFN responses.\",\n      \"evidence\": \"Co-IP, K33-linkage ubiquitination assay, and CRISPR/Cas9 knockout with viral survival assay in grass carp/rare minnow\",\n      \"pmids\": [\"40049566\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mammalian RIG-I regulation by RNF182 not tested\", \"Generalizability of K33 linkage to other substrates unknown\", \"Fish ortholog limits direct extrapolation\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Confirmed a pro-proliferative role for RNF182 in glioblastoma, though without mechanistic pathway placement.\",\n      \"evidence\": \"siRNA knockdown with proliferation assay, RT-qPCR, and Western blot in U87MG cells\",\n      \"pmids\": [\"42073544\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single method (loss-of-function phenotype) without substrate link\", \"No reconciliation with tumor-suppressive p65-degradation role\", \"Pathway not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RNF182 selects among its diverse substrates (ATP6V0C, p65, MFN2, RIG-I) and chooses ubiquitin linkage type (K48 vs K33) and degradation route (proteasomal vs autophagic) remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of substrate recognition\", \"No purified-protein reconstitution defining linkage specificity\", \"Context-dependent oncogenic vs tumor-suppressive roles unreconciled\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 2, 3, 5, 7]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2, 5, 7]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2, 3, 4]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 2, 5]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 7]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RELA\", \"ATP6V0C\", \"MFN2\", \"PCDHB14\", \"RIGI\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":6,"faith_total":6,"faith_pct":100.0}}