RNF152

RNF152 is a lysosome-anchored RING finger E3 ubiquitin ligase that functions as a negative regulator of mTORC1 signaling and modulates innate immune and Wnt pathways through both ligase-dependent and ligase-independent mechanisms. Its canonical E3 activity catalyzes K63-linked ubiquitination of RagA to recruit the GATOR1 GAP complex, thereby suppressing mTORC1 activation at the lysosome in response to amino acid availability, and it ubiquitinates the Ragulator subunit p18 for proteasomal degradation as a second means of mTORC1 inhibition (PMID:25936802, PMID:38706841). Independent of its ligase activity, RNF152 promotes MyD88 oligomerization to enhance TLR/IL-1R–NF-κB signaling and inhibits Wnt/β-catenin signaling by blocking Dishevelled polymerization in a transmembrane-domain-dependent manner (PMID:31930677, PMID:35410636). RNF152 also ubiquitinates IRAK1 and HSP27 for proteasomal degradation, linking it to suppression of lung adenocarcinoma metastasis and regulation of PI3K/AKT-driven inflammatory responses in synoviocytes (PMID:37717980, PMID:41413572).

1. 2010 Medium

   Establishing RNF152 as a bona fide lysosomal RING E3 ligase answered the basic question of where this uncharacterized RING-finger protein resides and whether it possesses intrinsic ubiquitin ligase activity.

   Evidence Fluorescence co-localization with LAMP3 and in vivo ubiquitination assays with RING/TM mutants in HeLa cells

   PMID:21203937

   Open questions at the time

   • No endogenous substrate was identified
   • Apoptosis phenotype upon overexpression lacked mechanistic detail
   • Self-ubiquitination versus trans-substrate activity not distinguished
2. 2015 High

   Identification of RagA as a direct substrate resolved how RNF152 connects to a major signaling pathway: K63-linked ubiquitination of RagA recruits GATOR1 to inactivate mTORC1, establishing RNF152 as a nutrient-sensing brake on mTORC1.

   Evidence Co-IP, in vivo ubiquitination with chain-type specificity, RagA ubiquitination-site mutants, RNF152-KO cells showing mTORC1 hyperactivation and reduced autophagy

   PMID:25936802

   Open questions at the time

   • How amino acid signals regulate RNF152 activity or stability was not defined
   • In vivo physiological consequences in animal models not tested
   • Relationship to the parallel TSC2-mediated regulation of mTORC1 was unresolved
3. 2020 High

   Discovery that RNF152 promotes MyD88 oligomerization independently of its E3 ligase activity revealed a scaffolding function and expanded its role beyond nutrient sensing into innate immunity.

   Evidence Reciprocal Co-IP, ligase-dead mutant retaining function, RNF152-deficient mice with impaired LPS-induced cytokine production and resistance to endotoxemia

   PMID:31930677

   Open questions at the time

   • Structural basis for RNF152-MyD88 interaction and oligomerization enhancement unknown
   • Whether lysosomal localization is required for this innate immune function was not addressed
   • Potential cross-talk between mTORC1 regulation and TLR signaling through RNF152 not explored
4. 2022 Medium

   Demonstrating that RNF152 inhibits Wnt/β-catenin signaling by blocking Dishevelled polymerization — again ligase-independently but requiring its transmembrane domain — established a second non-catalytic scaffolding role and suggested the membrane anchor is critical for protein-protein interaction functions.

   Evidence Wnt reporter assays, ligase-dead and TM-truncation mutants, Dishevelled polymerization assay, Xenopus morpholino knockdown with neural crest defects

   PMID:35410636

   Open questions at the time

   • Mechanism by which the transmembrane domain blocks Dvl polymerization not resolved at structural level
   • Relevance in mammalian Wnt-dependent tissues not confirmed
   • Whether RNF152 directly binds Dvl or acts indirectly was not fully discriminated
5. 2023 Medium

   Identification of IRAK1 as a ubiquitination substrate targeted for proteasomal degradation linked RNF152's ligase activity to suppression of fatty acid oxidation and metastasis in lung adenocarcinoma.

   Evidence Co-IP, ubiquitination assays, overexpression/knockdown with functional readouts, xenograft mouse model

   PMID:37717980

   Open questions at the time

   • Ubiquitin chain type on IRAK1 not specified
   • Whether IRAK1 degradation feeds back to the TLR–NF-κB axis regulated by RNF152 scaffolding was not tested
   • Single-lab finding without independent replication
6. 2024 Medium

   Demonstrating that RNF152 ubiquitinates the Ragulator subunit p18 for proteasomal degradation under fasting conditions revealed a second node of mTORC1 suppression at the lysosome, reinforcing the nutrient-sensing role.

   Evidence Ubiquitination assays, lentiviral silencing/overexpression, mTORC1 and glycolysis readouts, gallbladder cancer xenograft model

   PMID:38706841

   Open questions at the time

   • Relative contributions of RagA ubiquitination versus p18 degradation to mTORC1 suppression not dissected
   • Chain type on p18 not specified
   • Single-lab study in one cancer type
7. 2025 Medium

   Mapping HSP27 Lys114 as a ubiquitination site identified a new substrate and connected RNF152 to PI3K/AKT pathway activation in osteoarthritis-associated synoviocytes.

   Evidence IP-mass spectrometry, site-directed mutagenesis, co-localization imaging, in vivo AAV-siRNF152 in rat TMJOA model

   PMID:41413572

   Open questions at the time

   • Ubiquitin chain type on HSP27 not determined
   • How HSP27 degradation activates PI3K/AKT mechanistically is unclear
   • Single-lab, single disease model

• How RNF152 switches between its catalytic (E3 ligase) and non-catalytic (scaffolding) functions, and whether these are regulated by nutritional or inflammatory signals in an integrated manner, remains unknown.
• No structural information exists for RNF152 or its complexes
• Post-translational regulation of RNF152 itself (beyond self-ubiquitination) is largely uncharacterized
• Physiological role in whole-organism nutrient homeostasis has not been tested in RNF152-KO mice under metabolic challenge