Affinage

RNF152

E3 ubiquitin-protein ligase RNF152 · UniProt Q8N8N0

Length
203 aa
Mass
22.4 kDa
Annotated
2026-06-10
12 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RNF152 is a lysosome-anchored RING finger E3 ubiquitin ligase that functions as a negative regulator of mTORC1 signaling at the lysosomal surface (PMID:25936802, PMID:21203937). In an amino-acid-sensitive manner it catalyzes K63-linked polyubiquitination of RagA, which recruits the GATOR1 GAP complex and restrains mTORC1 activation; its loss causes mTORC1 hyperactivation and protects cells from starvation-induced autophagy (PMID:25936802). RNF152 also targets the Ragulator subunit p18 for ubiquitin-dependent proteasomal degradation, and under fasting this further dampens lysosomal mTORC1 activity (PMID:38706841). Beyond the mTORC1 axis, RNF152 ubiquitinates additional substrates to control inflammatory and oncogenic outputs: it drives K48-linked ubiquitination and degradation of IRAK1, reducing AKR1B10 transcription and suppressing fatty acid oxidation and metastasis (PMID:37717980), and it ubiquitinates HSP27 at Lys114 to promote its degradation, thereby activating PI3K/AKT signaling (PMID:41413572). Notably, RNF152 also acts through E3 ligase-independent, transmembrane-domain-dependent mechanisms: it enhances MyD88 oligomerization to positively regulate TLR/IL-1R signaling, with RNF152-deficient mice showing reduced inflammatory cytokines and resistance to endotoxemia (PMID:31930677), and it inhibits Dishevelled polymerization to suppress Wnt/β-catenin signaling (PMID:35410636). Consistent with its membrane localization and ubiquitination machinery, overexpression promotes apoptosis (PMID:21203937).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2010 Medium

    Established RNF152 as a bona fide lysosomal RING E3 ligase, answering whether it is catalytically active and where it acts in the cell.

    Evidence Co-localization with lysosomal marker LAMP3 and in vivo ubiquitination with RING/transmembrane domain deletion mutants, plus apoptosis readout on overexpression in HeLa cells

    PMID:21203937

    Open questions at the time
    • No physiological substrate identified at this stage
    • Apoptosis phenotype derives from overexpression without endogenous loss-of-function
    • Single lab
  2. 2015 High

    Identified the first physiological substrate and pathway, showing RNF152 negatively regulates mTORC1 by K63-ubiquitinating RagA to recruit GATOR1.

    Evidence Reciprocal Co-IP, RagA ubiquitination-site mutagenesis, and RNF152 knockout cells with mTORC1 activity and autophagy readouts

    PMID:25936802

    Open questions at the time
    • Upstream signal coupling RNF152 activity to amino-acid status not fully defined
    • Deubiquitinase counteracting the K63 chain not identified
  3. 2017 Medium

    Extended RNF152 function to development, showing its zebrafish ortholog is required for Delta-Notch signaling and NeuroD expression during neurogenesis.

    Evidence Morpholino knockdown in zebrafish with in situ hybridization for Notch pathway components and target genes

    PMID:29276941

    Open questions at the time
    • Pathway placement is correlative — no direct molecular substrate linking RNF152 to Notch
    • Whether the effect requires E3 ligase activity untested
  4. 2020 High

    Revealed an E3 ligase-independent role, demonstrating RNF152 positively regulates TLR/IL-1R signaling by promoting MyD88 oligomerization.

    Evidence Co-IP, MyD88 oligomerization and NF-κB reporter assays, ligase-dead mutant, and RNF152-deficient mouse endotoxemia model

    PMID:31930677

    Open questions at the time
    • Structural basis of how RNF152 enhances MyD88 oligomerization unknown
    • Reconciliation of pro-inflammatory MyD88 role with anti-inflammatory IRAK1 degradation not addressed
  5. 2022 Medium

    Defined a second non-catalytic, transmembrane-domain-dependent mechanism, showing RNF152 suppresses Wnt/β-catenin signaling by blocking Dishevelled polymerization.

    Evidence Gain- and loss-of-function in Xenopus embryos, Wnt reporter assays, ligase-dead and transmembrane-truncation mutants, and Dishevelled polymerization assays

    PMID:35410636

    Open questions at the time
    • Direct physical interaction interface with Dishevelled not mapped
    • Relevance in mammalian cells not established
    • Single lab
  6. 2023 Medium

    Identified IRAK1 as a degradative substrate, linking RNF152 to suppression of fatty acid oxidation and metastasis in lung adenocarcinoma.

    Evidence Co-IP, ubiquitination and protein stability assays, IRAK1 rescue, and mouse xenograft models with AKR1B10 and fatty acid oxidation readouts

    PMID:37717980

    Open questions at the time
    • Ubiquitination site on IRAK1 not mapped
    • Single lab
    • Connection to canonical IRAK1 signaling roles not explored
  7. 2024 Medium

    Showed RNF152 degrades the Ragulator subunit p18, providing a fasting-responsive second route to restraining lysosomal mTORC1.

    Evidence Co-IP, ubiquitination assays, proteasome inhibitor experiments, and RNF152 manipulation with mTORC1, glycolysis, and gemcitabine sensitivity readouts in gallbladder cancer cells

    PMID:38706841

    Open questions at the time
    • Ubiquitin linkage type and p18 acceptor sites not defined
    • Relationship between RagA and p18 substrate routes not integrated
    • Single lab
  8. 2024 Low

    Demonstrated RNF152 can be co-opted as a lysosomal tether by LYMTAC molecules to degrade KRAS G12D, exploiting its short-lived lysosomal membrane localization.

    Evidence Heterobifunctional small molecule treatment with KRAS relocalization imaging, phospho-ERK assays, and lysosomal degradation readouts (preprint)

    PMID:bio_10.1101_2024.09.08.611923

    Open questions at the time
    • Preprint; RNF152 used as an engineered tool, not mechanistically characterized
    • No mutagenesis of RNF152 itself
    • Single lab
  9. 2025 Medium

    Identified HSP27 as a site-specific substrate, connecting RNF152-mediated HSP27 degradation to PI3K/AKT activation in osteoarthritis.

    Evidence IP-MS, Co-IP, protein docking, Lys114 site-specific ubiquitination assays, and AAV-siRNF152 rat TMJOA model

    PMID:41413572

    Open questions at the time
    • Ubiquitin linkage type not specified
    • Single lab
    • Tissue-specificity versus other RNF152 functions not addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RNF152 toggles between its catalytic (substrate ubiquitination) and non-catalytic (MyD88/Dishevelled scaffolding) modes, and what selects among its diverse substrates in different tissues, remains unresolved.
  • No unifying model for substrate/mode selection
  • Regulation of RNF152 activity by upstream signals (amino acids, fasting) mechanistically incomplete
  • Structural basis of ligase-independent interactions unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016874 ligase activity 5 GO:0140096 catalytic activity, acting on a protein 4 GO:0060089 molecular transducer activity 2
Localization
GO:0005764 lysosome 3
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 1 R-HSA-9612973 Autophagy 1

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 RNF152 is a lysosome-anchored E3 ubiquitin ligase that targets RagA for K63-linked polyubiquitination in an amino-acid-sensitive manner, thereby recruiting the GATOR1 GAP complex to RagA and negatively regulating mTORC1 activation at the lysosome. RNF152 knockout results in hyperactivation of mTORC1 and protects cells from amino-acid-starvation-induced autophagy. Co-immunoprecipitation, ubiquitination assays, RagA ubiquitination-site mutagenesis, RNF152 knockout cells with mTORC1 activity and autophagy readouts Molecular cell High 25936802
2010 RNF152 is a canonical RING finger E3 ubiquitin ligase that localizes to lysosomes (co-localized with LAMP3), undergoes K48-linked polyubiquitination in a manner dependent on its RING finger and transmembrane domains, and promotes apoptosis when overexpressed in HeLa cells. Co-localization with lysosomal marker LAMP3, in vivo ubiquitination assays with domain deletion/mutation analysis, flow cytometry for apoptosis upon overexpression Protein & cell Medium 21203937
2020 RNF152 positively regulates TLR/IL-1R signaling by directly interacting with the adaptor protein MyD88 and enhancing MyD88 oligomerization, which is required for recruitment of downstream signaling components; this effect is independent of RNF152's E3 ligase activity. RNF152-deficient mice produce less inflammatory cytokines in response to LPS and are more resistant to LPS-induced lethal endotoxemia. Co-immunoprecipitation of RNF152 with MyD88, MyD88 oligomerization assays, RNF152 overexpression/knockdown with NF-κB reporter assays, RNF152-deficient mouse model with cytokine measurements and endotoxemia model EMBO reports High 31930677
2022 RNF152 acts as a negative regulator of Wnt/β-catenin signaling in Xenopus embryos by inhibiting Dishevelled polymerization in an E3 ligase-independent manner (requires the transmembrane domain but not ligase activity). Knockdown of RNF152 enhances Wnt-dependent transcriptional responses and neural crest formation, while overexpression inhibits β-catenin stabilization and target gene expression. Overexpression and morpholino knockdown in Xenopus embryos, Wnt-responsive reporter assays, ligase-dead and transmembrane-domain truncation mutants, Dishevelled polymerization assays BMB reports Medium 35410636
2023 RNF152 binds IRAK1 and promotes its K48-linked ubiquitination and proteasomal degradation, thereby reducing IRAK1-dependent transcription of AKR1B10 and suppressing fatty acid oxidation and metastasis in lung adenocarcinoma cells. Co-immunoprecipitation of RNF152 with IRAK1, ubiquitination assays, protein stability assays, RNF152 overexpression/knockdown with AKR1B10 expression and fatty acid oxidation readouts, IRAK1 rescue experiments, mouse xenograft models The American journal of pathology Medium 37717980
2024 Fasting-induced RNF152 ubiquitinates the Ragulator subunit p18, leading to its proteasomal degradation; loss of RNF152 increases lysosomal localization of p18 and mTORC1 activity, promoting glycolysis and gemcitabine resistance in gallbladder cancer cells. Co-immunoprecipitation, ubiquitination assays, proteasome inhibitor experiments, RNF152 overexpression/silencing with mTORC1 activity, glycolysis, and drug sensitivity readouts, lentiviral transfections iScience Medium 38706841
2025 RNF152 directly interacts with HSP27 and ubiquitinates it at Lys114, targeting HSP27 for proteasomal degradation; RNF152-mediated HSP27 degradation activates the PI3K/AKT pathway, driving fibroblast-like synoviocyte proliferation and pro-inflammatory cytokine release in temporomandibular joint osteoarthritis. Immunoprecipitation-mass spectrometry, co-immunoprecipitation, co-localization imaging, protein docking, site-specific ubiquitination (Lys114) assays, in vivo AAV-siRNF152 rat TMJOA model Arthritis research & therapy Medium 41413572
2017 Zebrafish rnf152 (ortholog of human RNF152) is required for Delta-Notch signaling and NeuroD expression during brain development; knockdown abolishes NeuroD expression in retinal layers and reduces deltaD, notch1a, notch3, and Notch target genes her4 and ascl1a in midbrain, hindbrain, and rhombomeres. Morpholino knockdown in zebrafish embryos, whole-mount in situ hybridization for neuroD, deltaD, notch1a, notch3, her4, ascl1a Molecules and cells Medium 29276941
2024 RNF152, as a short-lived lysosomal membrane protein, can be co-opted by bifunctional LYMTAC small molecules to tether KRAS G12D to the lysosomal membrane, inducing KRAS relocalization, inhibition of downstream phospho-ERK signaling, and lysosomal degradation of KRAS G12D. Heterobifunctional small molecule (LYMTAC) treatment, KRAS relocalization imaging, phospho-ERK signaling assays, lysosomal degradation assays in cell lines bioRxivpreprint Low bio_10.1101_2024.09.08.611923
2021 Overexpression of RNF152 in RKO colon cancer cells increases apoptosis and sensitizes cells to NO donor-induced apoptosis, accompanied by decreased expression of anti-apoptotic proteins Bcl-XL and Bcl-2. RNF152 overexpression in RKO cells, flow cytometry for apoptosis, western blot for Bcl-2 and Bcl-XL Zhonghua zhong liu za zhi Low 34034471

Source papers

Stage 0 corpus · 12 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 The ubiquitination of rag A GTPase by RNF152 negatively regulates mTORC1 activation. Molecular cell 106 25936802
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
2010 RNF152, a novel lysosome localized E3 ligase with pro-apoptotic activities. Protein & cell 35 21203937
2020 RNF152 positively regulates TLR/IL-1R signaling by enhancing MyD88 oligomerization. EMBO reports 25 31930677
2017 Rnf152 Is Essential for NeuroD Expression and Delta-Notch Signaling in the Zebrafish Embryos. Molecules and cells 12 29276941
2021 Probiotic-derived p8 protein induce apoptosis via regulation of RNF152 in colorectal cancer cells. American journal of cancer research 10 33791151
2023 RNF152 Suppresses Fatty Acid Oxidation and Metastasis of Lung Adenocarcinoma by Inhibiting IRAK1-Mediated AKR1B10 Expression. The American journal of pathology 6 37717980
2022 RNF152 negatively regulates Wnt/β-catenin signaling in Xenopus embryos. BMB reports 4 35410636
2024 Fasting-induced RNF152 resensitizes gallbladder cancer cells to gemcitabine by inhibiting mTORC1-mediated glycolysis. iScience 2 38706841
2025 Mast cell tryptase-PAR2 axis promotes ovarian fibrosis through RNF152-mediated stabilization of Bcl-xL. Journal of ovarian research 1 40474218
2025 RNF152-mediated, ubiquitin-dependent degradation of HSP27 activates the PI3K/AKT pathway, driving synovial inflammatory cascades in TMJOA. Arthritis research & therapy 0 41413572
2021 [Effect of RNF152 on NO induced apoptosis of colon cancer cells]. Zhonghua zhong liu za zhi [Chinese journal of oncology] 0 34034471

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