RNF182

RNF182 is a RING finger E3 ubiquitin ligase that ubiquitinates multiple substrates to regulate NF-κB signaling, neurotransmitter release, mitochondrial dynamics, and innate immunity. RNF182 catalyzes K48-linked polyubiquitination of the NF-κB subunit p65, targeting it for both proteasomal and p62-mediated autophagic degradation, which suppresses NF-κB-dependent transcription of genes including SLC7A11 and CD274 (PDL1) in cancer cells and inflammatory contexts (PMID:35688944, PMID:37249301, PMID:35458235, PMID:41503854). RNF182 also ubiquitinates ATP6V0C to promote its proteasomal degradation, linking it to regulation of V-ATPase-dependent neurotransmitter release, and ubiquitinates MFN2 to drive mitochondrial dysfunction in renal fibrosis (PMID:18298843, PMID:41461638). RNF182 expression is transcriptionally regulated by MeCP2 via CpG methylation and is repressed by the carcinogen benzo[a]pyrene through AhR-dependent and AhR-independent promoter hypermethylation, with loss of RNF182 promoting NSCLC cell proliferation (PMID:20569274, PMID:36686776).

1. 2008 High

   Establishing RNF182 as a functional E3 ubiquitin ligase with a defined neuronal substrate resolved the question of whether this brain-enriched RING finger protein possesses catalytic activity and identified ATP6V0C as its first target for proteasomal degradation.

   Evidence In vitro ubiquitination assay, yeast two-hybrid, co-immunoprecipitation, and overexpression in cultured cells

   PMID:18298843

   Open questions at the time

   • Physiological consequence of ATP6V0C degradation on neurotransmitter release not directly measured
   • No in vivo loss-of-function validation in neuronal tissue
   • Structural basis of RNF182–ATP6V0C recognition unknown
2. 2010 Medium

   Identifying RNF182 as a direct transcriptional target of MeCP2 via CpG methylation connected RNF182 regulation to the epigenetic machinery governing neuronal gene expression.

   Evidence ChIP demonstrating MeCP2 binding to methylated RNF182 CpG island, bisulfite sequencing, expression profiling in MeCP2-mutant fibroblasts

   PMID:20569274

   Open questions at the time

   • Functional consequence of MeCP2-dependent RNF182 regulation on neuronal survival not directly tested
   • Whether MeCP2 activates or represses RNF182 in neurons in vivo remains unclear
   • Single cell-line system (fibroblasts, not neurons)
3. 2018 Medium

   Demonstrating that RNF182 silencing activates mTOR signaling and reduces cardiomyocyte apoptosis in ischemia-reperfusion injury placed RNF182 upstream of mTOR as a negative regulator in cardiac pathology, extending its function beyond the nervous system.

   Evidence shRNA knockdown in rat myocardial ischemia-reperfusion model with pharmacological mTOR inhibition rescue

   PMID:30450663

   Open questions at the time

   • Direct substrate linking RNF182 to mTOR pathway suppression not identified
   • Single lab, no independent replication
   • Mechanism by which RNF182 inhibits mTOR signaling is unknown
4. 2022 High

   Identification of p65 as a direct RNF182 substrate undergoing K48-linked ubiquitination and degradation established the molecular mechanism by which RNF182 suppresses NF-κB signaling, linking this to ferroptosis induction in hepatocellular carcinoma and to anti-inflammatory effects in tendinopathy.

   Evidence Reciprocal Co-IP, K48-linkage ubiquitination assays, ChIP on SLC7A11 promoter, functional rescue experiments in cancer cells and tenocytes, in vivo tendinopathy model

   PMID:35458235 PMID:35688944

   Open questions at the time

   • Whether proteasomal vs. autophagic degradation of p65 predominates in different cell types is unresolved
   • Specific lysine residues on p65 targeted by RNF182 not mapped
5. 2023 High

   Extending p65 ubiquitination to immune evasion, showing that RNF182-mediated p65 degradation suppresses PDL1 transcription and restores CD8+ T cell cytotoxicity, broadened RNF182's tumor-suppressive role to immunomodulation in lung adenocarcinoma.

   Evidence Co-IP, ChIP-qPCR on PDL1 promoter, luciferase reporter, co-culture cytotoxicity assays, in vivo xenograft

   PMID:37249301

   Open questions at the time

   • Whether RNF182 affects anti-tumor immunity in immunocompetent models is untested
   • Contribution relative to other p65 E3 ligases not assessed
6. 2023 Medium

   Demonstrating that benzo[a]pyrene represses RNF182 via AhR-dependent transcriptional repression and AhR-independent promoter hypermethylation linked carcinogen exposure to loss of RNF182 tumor-suppressive function in NSCLC.

   Evidence RT-qPCR, ChIP for AhR binding, bisulfite genomic sequencing, RNF182 overexpression rescue of proliferation in NSCLC cell lines

   PMID:36686776

   Open questions at the time

   • In vivo relevance of BaP-mediated RNF182 silencing in lung carcinogenesis not shown
   • Whether RNF182 loss promotes NSCLC through p65 stabilization specifically was not tested
7. 2025 Medium

   Identification of RIG-I as a substrate for K33-linked ubiquitination by the fish ortholog of RNF182 expanded its substrate repertoire to innate immune receptors and revealed a non-canonical ubiquitin linkage type for this ligase.

   Evidence Co-IP, ubiquitin linkage-type analysis, CRISPR/Cas9 knockout in rare minnow with in vivo viral challenge

   PMID:40049566

   Open questions at the time

   • Whether mammalian RNF182 also ubiquitinates RIG-I is unknown
   • K33-linked ubiquitination mechanism and E2 partner not defined
   • Fish ortholog; direct extrapolation to human requires validation
8. 2026 Medium

   Discovery that RNF182 ubiquitinates MFN2 to drive mitochondrial dysfunction in renal fibrosis identified a fourth substrate class and linked RNF182 to mitochondrial quality control.

   Evidence In vivo mouse UUO and 5/6Nx models, TGF-β1-stimulated kidney cells, RNF182 inhibition rescue, mitochondrial respiration and ATP measurements

   PMID:41461638

   Open questions at the time

   • Ubiquitin linkage type on MFN2 not determined
   • Whether RNF182-MFN2 axis operates in tissues beyond kidney is unknown
   • Single lab finding

• The structural basis for RNF182 substrate selectivity across its diverse targets (ATP6V0C, p65, MFN2, RIG-I), its preferred E2 partners, and its physiological role in mammalian brain development remain uncharacterized.
• No structural or biochemical reconstitution of RNF182 with any substrate
• No mammalian knockout phenotype reported
• E2 ubiquitin-conjugating enzyme preference not identified