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RNF182

E3 ubiquitin-protein ligase RNF182 · UniProt Q8N6D2

Length
247 aa
Mass
27.4 kDa
Annotated
2026-06-10
20 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2008 High

    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

    PMID:18298843

    Open questions at the time
    • Physiological consequences of ATP6V0C turnover not defined
    • E2 partner specificity in cells not resolved
    • No structural basis for substrate selection
  2. 2010 Low

    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

    PMID:20569274

    Open questions at the time
    • Functional link to apoptosis inferred, not directly demonstrated
    • Direction of regulation across cell types unclear
    • No connection to RNF182 ligase activity established
  3. 2018 Medium

    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

    PMID:30450663

    Open questions at the time
    • Direct substrate connecting RNF182 to mTOR not identified
    • Epistasis based on expression markers, not biochemistry
    • Mammalian-cell mechanism not reconstituted
  4. 2022 Medium

    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

    PMID:35688944

    Open questions at the time
    • No in vitro reconstitution with purified proteins
    • Direct vs. PCDHB14-dependent ubiquitination not separated
    • Single-lab finding
  5. 2022 Medium

    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

    PMID:35458235

    Open questions at the time
    • Switch between proteasomal and autophagic fate of p65 unexplained
    • Mechanism of friedelin-induced RNF182 recruitment unknown
    • Not independently replicated
  6. 2023 Medium

    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

    PMID:37249301

    Open questions at the time
    • Direct ubiquitination of p65 not reconstituted
    • Determinants of RNF182 abundance in tumors not defined
    • Single-lab finding
  7. 2025 Medium

    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

    PMID:41461638

    Open questions at the time
    • Ubiquitin linkage type on MFN2 not specified
    • Substrate selectivity vs. p65 not addressed
    • Single-lab finding
  8. 2025 Medium

    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

    PMID:40049566

    Open questions at the time
    • Mammalian RIG-I regulation by RNF182 not tested
    • Generalizability of K33 linkage to other substrates unknown
    • Fish ortholog limits direct extrapolation
  9. 2026 Low

    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

    PMID:42073544

    Open questions at the time
    • Single method (loss-of-function phenotype) without substrate link
    • No reconciliation with tumor-suppressive p65-degradation role
    • Pathway not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • No structural model of substrate recognition
  • No purified-protein reconstitution defining linkage specificity
  • Context-dependent oncogenic vs tumor-suppressive roles unreconciled

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 6 GO:0140096 catalytic activity, acting on a protein 5 GO:0016874 ligase activity 1
Localization
GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-168256 Immune System 2 R-HSA-5357801 Programmed Cell Death 2
Partners
ATP6V0CMFN2PCDHB14RELARIGI

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 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. In vitro ubiquitination assay, yeast two-hybrid, co-immunoprecipitation, overexpression with protein degradation assay Molecular neurodegeneration High 18298843
2022 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. Co-immunoprecipitation, Western blot (ubiquitination assay), chromatin immunoprecipitation, reporter assay, loss-of-function and overexpression experiments Oncogene Medium 35688944
2023 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. Co-immunoprecipitation, Western blot (ubiquitination), ChIP-qPCR, luciferase reporter assay, CD8+ T cell co-culture cytotoxicity assay, in vivo xenograft Immunity, inflammation and disease Medium 37249301
2022 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. Co-immunoprecipitation, ubiquitination assay (K48-linkage-specific), autophagy flux assay, pharmacological inhibitor rescue, in vivo tendinopathy mouse model Nutrients Medium 35458235
2026 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. Co-immunoprecipitation, Western blot, in vivo cervical spine instability mouse model, in vitro NP cell assays Journal of cellular and molecular medicine Medium 41503854
2025 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. In vitro ubiquitination/degradation assay, rescue experiments (RNF182 inhibition), in vivo UUO and 5/6Nx mouse models, Western blot Cell death discovery Medium 41461638
2018 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. shRNA knockdown in rat MIRI model, pharmacological rescue with mTOR inhibitor, Western blot, echocardiography, apoptosis assays Journal of cellular biochemistry Medium 30450663
2025 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. Co-immunoprecipitation, linkage-specific ubiquitination assay (K33), CRISPR/Cas9 knockout, viral infection survival assay, cellular localization analysis Fish & shellfish immunology Medium 40049566
2026 siRNA-mediated silencing of RNF182 in U87MG glioblastoma cells significantly reduced cell proliferation, establishing a functional role for RNF182 in promoting glioblastoma cell growth. siRNA knockdown, proliferation assay (cell counting), RT-qPCR, Western blot Cancers Low 42073544
2010 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. Microarray gene expression profiling, RT-qPCR, chromatin immunoprecipitation (ChIP), bisulfite sequencing Journal of cellular and molecular medicine Low 20569274

Source papers

Stage 0 corpus · 20 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2022 PCDHB14 promotes ferroptosis and is a novel tumor suppressor in hepatocellular carcinoma. Oncogene 54 35688944
2008 A novel brain-enriched E3 ubiquitin ligase RNF182 is up regulated in the brains of Alzheimer's patients and targets ATP6V0C for degradation. Molecular neurodegeneration 53 18298843
2020 The Role of Tissue-Specific Ubiquitin Ligases, RNF183, RNF186, RNF182 and RNF152, in Disease and Biological Function. International journal of molecular sciences 49 32486221
2023 Identifying potential biomarkers of idiopathic pulmonary fibrosis through machine learning analysis. Scientific reports 40 37783761
2010 Cell cloning-based transcriptome analysis in Rett patients: relevance to the pathogenesis of Rett syndrome of new human MeCP2 target genes. Journal of cellular and molecular medicine 27 20569274
2014 An integrative CGH, MSI and candidate genes methylation analysis of colorectal tumors. PloS one 26 24475022
2022 Friedelin Alleviates the Pathogenesis of Collagenase-Induced Tendinopathy in Mice by Promoting the Selective Autophagic Degradation of p65. Nutrients 19 35458235
2021 Ammonia induces autophagy via circ-IFNLR1/miR-2188-5p/RNF182 axis in tracheas of chickens. BioFactors (Oxford, England) 16 34652043
2020 Identification and verification of EOMEs regulated network in Alopecia areata. International immunopharmacology 11 32353685
2018 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. Journal of cellular biochemistry 11 30450663
2024 SIRPG promotes lung squamous cell carcinoma pathogenesis via M1 macrophages: a multi-omics study integrating data and Mendelian randomization. Frontiers in oncology 9 38894865
2023 RNF182 induces p65 ubiquitination to affect PDL1 transcription and suppress immune evasion in lung adenocarcinoma. Immunity, inflammation and disease 8 37249301
2023 Inhibition of RNF182 mediated by Bap promotes non-small cell lung cancer progression. Frontiers in oncology 6 36686776
2023 The role of ferroptosis-related genes in airway epithelial cells of asthmatic patients based on bioinformatics. Medicine 5 36862916
2026 Friedelin Ameliorates Nucleus Pulposus Inflammation by Increasing p65 Autophagic Degradation to Inhibit NF-κB Signalling Pathway. Journal of cellular and molecular medicine 1 41503854
2025 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). Fish & shellfish immunology 1 40049566
2026 Identifying the strongest novel gene-respiratory disease interactions for rheumatoid arthritis risk. Seminars in arthritis and rheumatism 0 41713227
2026 Diabetes affects the composition of the respiratory tract microbiome and transcriptome in patients with viral pneumonia. Microbiology spectrum 0 41940665
2026 Overexpression of the Ubiquitin Ligase RNF182 Is Associated with High-Grade Gliomas. Cancers 0 42073544
2025 IL‑1 receptor antagonism attenuates renal fibrosis via RNF182‑driven MFN2 destabilization and mitochondrial dysfunction. Cell death discovery 0 41461638

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