Affinage

RNF183

E3 ubiquitin-protein ligase RNF183 · UniProt Q96D59

Length
192 aa
Mass
21.6 kDa
Annotated
2026-04-28
17 papers in source corpus 13 papers cited in narrative 13 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RNF183 is a transmembrane RING finger E3 ubiquitin ligase that controls cell survival, inflammatory signaling, and ion transporter turnover by targeting multiple substrates for either proteasomal or lysosomal degradation. It catalyzes K48-linked polyubiquitination of IκBα, Bcl-xL, SHP2, and PKM2 to promote their proteasomal destruction—thereby activating NF-κB signaling, sensitizing cells to ER stress–induced apoptosis, enhancing STAT3 pathway activity, and modulating glycolytic metabolism, respectively (PMID:26818663, PMID:29507230, PMID:35104174, PMID:40072093)—and K63-linked polyubiquitination of DR5, Na,K-ATPase β1, and NKCC1 to direct their lysosomal degradation, regulating TRAIL-induced apoptosis and renal ion homeostasis under hypertonic stress (PMID:31889078, PMID:31732153, PMID:41942761). RNF183 expression is transcriptionally driven by NFAT5 in the renal medulla in response to hypertonicity, post-transcriptionally stabilized by IRE1α-mediated suppression of miR-7 during ER stress, epitranscriptomically regulated by METTL3/IGF2BP2-dependent m6A modification, and its protein stability is governed by Sec16A-mediated protection from ERAD and FBXO5–SCF complex–mediated proteasomal degradation (PMID:30413537, PMID:29507230, PMID:40072093, PMID:29300766, PMID:38212299).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2016 Medium

    Establishing that RNF183 functions as a pro-inflammatory E3 ligase by identifying IκBα as a direct ubiquitination substrate whose degradation activates NF-κB, and that miR-7 negatively regulates RNF183 expression, provided the first mechanistic link between this RING finger protein and intestinal inflammation.

    Evidence siRNA knockdown, overexpression, Co-IP of IκBα, miR-7 mimic/inhibitor experiments in intestinal cell lines

    PMID:26818663

    Open questions at the time
    • IκBα ubiquitination linkage type not specified
    • no in vivo intestinal inflammation model
    • single-lab finding without independent replication
  2. 2017 Medium

    Demonstrating that the NF-κB–activating function of RNF183 requires intact E3 ligase catalytic activity and drives IL-8 transcription to promote colorectal cancer cell migration and invasion extended the pro-inflammatory role to a cancer-promoting context.

    Evidence E3 ligase activity-dead mutant, NF-κB inhibitor, migration/invasion assays, xenograft model in colorectal cancer cells

    PMID:28796265

    Open questions at the time
    • direct ubiquitination substrate in this cancer context not formally identified
    • single-lab study
  3. 2018 High

    Identification of RNF183 as an ER-localized transmembrane E3 ligase upregulated by sustained ER stress through IRE1α-mediated suppression of miR-7, with Bcl-xL as a direct ubiquitination substrate targeted for proteasomal degradation, established the mechanistic basis for ER stress–induced apoptosis via RNF183.

    Evidence In vitro ubiquitination assay, Co-IP, subcellular fractionation, IRE1α inhibition, fluorescence imaging in multiple cell lines

    PMID:29507230

    Open questions at the time
    • ubiquitination site on Bcl-xL not mapped
    • contribution relative to other Bcl-xL regulatory mechanisms not quantified
  4. 2018 Medium

    Discovery that Sec16A physically interacts with RNF183 and protects it from ERAD-mediated degradation, together with confirmation that RNF183 localizes to the ER, Golgi, and lysosomes, revealed a protein stability control mechanism and clarified the subcellular distribution enabling RNF183's diverse substrate access.

    Evidence Co-IP, subcellular localization imaging, siRNA knockdown of Sec16A with ERAD readout

    PMID:29300766

    Open questions at the time
    • structural basis of Sec16A–RNF183 interaction not defined
    • single-lab study without independent confirmation
  5. 2018 High

    Showing that NFAT5 directly binds the RNF183 promoter to drive kidney-specific, hypertonicity-induced expression established the transcriptional logic governing RNF183 in the renal medulla and linked its loss to increased apoptosis under osmotic stress.

    Evidence ChIP, luciferase reporter with binding-site mutation, caspase-3 activation in mIMCD-3 cells

    PMID:30413537

    Open questions at the time
    • identity of the RNF183 substrate(s) mediating renal anti-apoptotic protection was unknown at this stage
  6. 2019 High

    Identification of DR5 and Na,K-ATPase β1 as K63-linked and lysosomal-targeted ubiquitination substrates expanded RNF183's repertoire beyond proteasomal degradation and showed it regulates both TRAIL-mediated apoptosis and plasma membrane ion transporter turnover under hypertonic conditions.

    Evidence K63-linkage-specific ubiquitination assays, lysosomal inhibitor rescue, BirA proximity biotinylation (Na,K-ATPase β1), Co-IP, caspase activation assays

    PMID:31732153 PMID:31889078

    Open questions at the time
    • how RNF183 distinguishes between K48- and K63-linkage on different substrates is unknown
    • E2 conjugating enzyme identity not determined
  7. 2019 High

    In vivo validation using CRISPR/Cas9 RNF183-GFP knock-in mice confirmed renal medullary collecting duct expression, NFAT5-dependent regulation by tonicity (furosemide treatment), and colocalization with aquaporin-2, establishing the physiological context of RNF183 function in the kidney.

    Evidence CRISPR/Cas9 knock-in mouse, immunofluorescence, furosemide in vivo perturbation

    PMID:31053298

    Open questions at the time
    • no full knockout mouse phenotype reported
    • functional consequence of RNF183 loss in vivo not assessed at this stage
  8. 2022 Medium

    Demonstrating that RNF183 ubiquitinates and degrades SHP2 to activate STAT3 signaling and promote lung adenocarcinoma proliferation broadened the oncogenic signaling roles of RNF183 beyond NF-κB.

    Evidence Co-IP, ubiquitination assay, siRNA knockdown, in vivo xenograft in lung adenocarcinoma cells

    PMID:35104174

    Open questions at the time
    • ubiquitin linkage type on SHP2 not determined
    • single-lab finding
  9. 2022 Medium

    Placing RNF183 downstream of cathepsin D inhibition in a positive feedback loop with NF-κB, where NF-κB induces RNF183 which then degrades Bcl-xL, clarified how RNF183 can be pharmacologically leveraged to sensitize cancer cells to apoptosis.

    Evidence siRNA knockdown, western blot, xenograft model, tissue correlation analysis

    PMID:35121737

    Open questions at the time
    • whether NF-κB directly binds the RNF183 promoter was not demonstrated
    • single-lab study
  10. 2024 High

    Identifying FBXO5–SCF as the E3 ligase complex that ubiquitinates and degrades RNF183 itself, regulated by E2F2 during ER stress, established a negative feedback circuit controlling RNF183 protein levels and apoptotic output.

    Evidence Co-IP, F-box deletion mutant, ubiquitination assay, rescue experiments, in vivo tumor model

    PMID:38212299

    Open questions at the time
    • ubiquitination sites on RNF183 targeted by FBXO5 not mapped
    • interplay between FBXO5-mediated and Sec16A-mediated stability control not addressed
  11. 2025 Medium

    Discovery that RNF183 directly ubiquitinates PKM2 for proteasomal degradation and that RNF183 mRNA stability is regulated by METTL3/IGF2BP2-dependent m6A modification in podocytes added an epitranscriptomic regulatory layer and a metabolic substrate to RNF183 biology.

    Evidence Co-IP, LC-MS substrate identification, ubiquitination assay, m6A inhibitor treatment, overexpression/knockdown in podocytes under high glucose

    PMID:40072093

    Open questions at the time
    • m6A modification sites on RNF183 mRNA not mapped
    • in vivo diabetic nephropathy model not included
    • single-lab finding
  12. 2026 High

    Identification of NKCC1 as a K63-linked ubiquitination substrate directed to lysosomal degradation by RNF183, combined with CRISPR knockout evidence that RNF183 loss increases hypertonic cell death, established RNF183 as a key regulator of intracellular Na⁺ homeostasis and cell survival in renal collecting duct cells.

    Evidence K63-linkage-specific ubiquitination assay, CRISPR/Cas9 knockout in mIMCD-3 cells, lysosomal inhibitor rescue, intracellular Na⁺ measurement, caspase-3 cleavage assay

    PMID:41942761

    Open questions at the time
    • in vivo renal phenotype of RNF183 knockout not yet reported
    • how RNF183 is itself regulated under hypertonicity at the protein level (beyond NFAT5 transcription) remains unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • The E2 conjugating enzyme(s) used by RNF183, the structural basis for its dual K48/K63 linkage specificity, and the full phenotype of RNF183 loss in a whole-organism model remain unresolved.
  • E2 enzyme partner(s) not identified
  • no crystal or cryo-EM structure of RNF183 or RNF183–substrate complexes
  • no complete knockout mouse phenotypic characterization
  • how substrate selection between K48 and K63 linkage is determined is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 8 GO:0016874 ligase activity 7
Localization
GO:0005783 endoplasmic reticulum 2 GO:0005764 lysosome 1 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-392499 Metabolism of proteins 8 R-HSA-162582 Signal Transduction 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-168256 Immune System 2 R-HSA-382551 Transport of small molecules 2
Partners
ATP1B1BCL2L1NFKBIAPKMPTPN11SEC16ASLC12A2TNFRSF10B

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 RNF183 promotes intestinal inflammation by ubiquitinating IκBα, leading to its degradation and consequent NF-κB activation; this activity is negatively regulated by miR-7, which suppresses RNF183 expression siRNA knockdown, plasmid transfection, immunoprecipitation, miRNA mimic/inhibitor transfection Journal of Crohn's & colitis Medium 26818663
2017 RNF183 activates the NF-κB signaling pathway through p65 and stimulates IL-8 transcription to promote colorectal cancer cell migration and invasion; this function requires its E3 ubiquitin ligase activity siRNA knockdown, small molecule NF-κB inhibitor, E3 ligase activity-dead mutant, in vitro migration/invasion assays, in vivo xenograft Cell death & disease Medium 28796265
2018 RNF183 is an ER-localized transmembrane RING finger E3 ubiquitin ligase that is upregulated by sustained ER stress in an IRE1α-dependent manner (via IRE1-mediated reduction of miR-7); RNF183 interacts with and polyubiquitinates Bcl-xL, targeting it for proteasomal degradation and thereby inducing apoptosis Co-immunoprecipitation, in vitro ubiquitination assay, subcellular fractionation/fluorescence imaging, siRNA knockdown, overexpression, IRE1α inhibition Proceedings of the National Academy of Sciences of the United States of America High 29507230
2018 RNF183 predominantly localizes to the ER, Golgi, and lysosome; it interacts with Sec16A (a COPII vesicle formation protein) via Sec16A's central conserved domain, and Sec16A stabilizes RNF183 by protecting it from ERAD-mediated degradation Co-immunoprecipitation, subcellular localization imaging, siRNA knockdown, ERAD assay PloS one Medium 29300766
2018 NFAT5 transcription factor directly binds to a conserved motif in the RNF183 promoter (-3,466 to -3,136 bp upstream) and drives kidney-specific, hypertonicity-induced RNF183 expression; RNF183 knockdown increases hypertonicity-induced apoptosis in renal medullary cells siRNA knockdown, luciferase reporter assay, ChIP assay, promoter mutation analysis, caspase-3 activation assay The Journal of biological chemistry High 30413537
2019 RNF183 mediates K63-linked ubiquitination of death receptor 5 (DR5), targeting it for lysosomal degradation; this promotes TRAIL-induced caspase-8 and caspase-3 activation and apoptosis Co-immunoprecipitation, ubiquitination assay (K63-linkage specific), lysosomal inhibitor treatment, caspase activation assay, siRNA knockdown Scientific reports High 31889078
2019 RNF183 ubiquitinates the Na,K-ATPase β1 subunit (but not α1), causing lysosomal co-degradation of both α1 and β1 subunits; RNF183 translocates Na,K-ATPase from the plasma membrane to lysosomes under hypertonic conditions BirA proximity biotinylation, Co-immunoprecipitation, in vitro ubiquitination assay, siRNA knockdown, chloroquine lysosomal inhibitor treatment, stable cell line overexpression Biochemical and biophysical research communications High 31732153
2019 RNF183 expression in renal medullary collecting ducts is regulated in vivo by NFAT5 in response to tonicity; furosemide treatment decreases renal medullary tonicity, reduces NFAT5 activity, and decreases RNF183 expression; RNF183-GFP knock-in mice show RNF183 colocalizes with aquaporin-2 in collecting duct cells CRISPR/Cas9 knock-in mice (RNF183-GFP), immunofluorescence, furosemide in vivo treatment, mIMCD-3 cell reporter assay Biochemical and biophysical research communications High 31053298
2022 RNF183 ubiquitinates SHP2 (a negative regulator of STAT3), leading to its degradation and consequent STAT3 pathway activation, which promotes lung adenocarcinoma cell proliferation Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, in vivo xenograft model Cell cycle (Georgetown, Tex.) Medium 35104174
2022 Cathepsin D inhibition upregulates RNF183 expression via NF-κB activation, which in turn destabilizes Bcl-xL through RNF183 E3 ligase activity, sensitizing cancer cells to anticancer drug-induced apoptosis siRNA knockdown, western blot, xenograft model, correlation analysis in tissue samples Cell death & disease Medium 35121737
2024 FBXO5, an F-box protein whose expression is regulated by E2F2 downstream of ER stress, directly binds RNF183 and promotes its ubiquitin-dependent proteasomal degradation, thereby counteracting RNF183-mediated apoptosis; FBXO5 ΔF-box mutant cannot degrade RNF183, confirming SCF complex requirement Co-immunoprecipitation, ubiquitination assay, F-box deletion mutant, siRNA knockdown, overexpression rescue experiments, in vivo tumor model Cell death & disease High 38212299
2025 RNF183 directly ubiquitinates PKM2 (M2 pyruvate kinase), targeting it for proteasomal degradation; RNF183 expression is regulated by m6A methylation via METTL3 writer and IGF2BP2 reader; in podocytes under high glucose, reduced METTL3/IGF2BP2 lowers RNF183, decreasing PKM2 ubiquitination and aggravating podocyte injury Co-immunoprecipitation, LC-MS, ubiquitination assay, m6A inhibitor (MA2) treatment, overexpression/knockdown, transcriptome sequencing Cells Medium 40072093
2026 RNF183 promotes K63-linked ubiquitination of NKCC1 (Na-K-2Cl co-transporter 1), leading to its lysosomal degradation; this regulates intracellular Na+ homeostasis under hypertonic conditions in renal collecting duct cells, and knockout of RNF183 in mIMCD-3 cells increases hypertonic-induced caspase-3 cleavage and cell death Co-immunoprecipitation, K63-linkage specific ubiquitination assay, lysosomal inhibitor treatment, CRISPR/Cas9 knockout, intracellular Na+ measurement, caspase-3 cleavage assay Communications biology High 41942761

Source papers

Stage 0 corpus · 17 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 RNF183 promotes proliferation and metastasis of colorectal cancer cells via activation of NF-κB-IL-8 axis. Cell death & disease 58 28796265
2016 E3 Ubiquitin ligase RNF183 Is a Novel Regulator in Inflammatory Bowel Disease. Journal of Crohn's & colitis 55 26818663
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
2018 Transmembrane E3 ligase RNF183 mediates ER stress-induced apoptosis by degrading Bcl-xL. Proceedings of the National Academy of Sciences of the United States of America 44 29507230
2022 Cathepsin D as a potential therapeutic target to enhance anticancer drug-induced apoptosis via RNF183-mediated destabilization of Bcl-xL in cancer cells. Cell death & disease 36 35121737
2023 The YTHDC1/GLUT3/RNF183 axis forms a positive feedback loop that modulates glucose metabolism and bladder cancer progression. Experimental & molecular medicine 29 37258572
2024 FBXO5-mediated RNF183 degradation prevents endoplasmic reticulum stress-induced apoptosis and promotes colon cancer progression. Cell death & disease 18 38212299
2018 NFAT5 up-regulates expression of the kidney-specific ubiquitin ligase gene Rnf183 under hypertonic conditions in inner-medullary collecting duct cells. The Journal of biological chemistry 18 30413537
2019 Inflammatory bowel disease-associated ubiquitin ligase RNF183 promotes lysosomal degradation of DR5 and TRAIL-induced caspase activation. Scientific reports 14 31889078
2018 Sec16A, a key protein in COPII vesicle formation, regulates the stability and localization of the novel ubiquitin ligase RNF183. PloS one 11 29300766
2021 Moxibustion Inhibits the Expression of Colonic NLRP3 through miR7/RNF183/NF-κB Signaling Pathway in UC Rats. Evidence-based complementary and alternative medicine : eCAM 10 34777536
2019 Hypertonicity-responsive ubiquitin ligase RNF183 promotes Na, K-ATPase lysosomal degradation through ubiquitination of its β1 subunit. Biochemical and biophysical research communications 10 31732153
2019 Renal medullary tonicity regulates RNF183 expression in the collecting ducts via NFAT5. Biochemical and biophysical research communications 7 31053298
2022 Knockdown of RNF183 suppressed proliferation of lung adenocarcinoma cells via inactivating the STAT3 signaling pathway. Cell cycle (Georgetown, Tex.) 5 35104174
2024 RNF183 Promotes Colon Cancer Cell Stemness through Fatty Acid Oxidation. Nutrition and cancer 4 38044546
2025 Modification of RNF183 via m6A Methylation Mediates Podocyte Dysfunction in Diabetic Nephropathy by Regulating PKM2 Ubiquitination and Degradation. Cells 3 40072093
2026 Hypertonicity-induced RNF183 targets NKCC1 to protect kidney collecting duct cells but induces apoptosis in colon cells. Communications biology 0 41942761