RNF145

RNF145 is an ER-resident RING-type E3 ubiquitin ligase that integrates sterol and fatty acid signals to coordinate cholesterol biosynthesis, SREBP-2 activation, and membrane lipid homeostasis. Transcriptionally induced by LXR (PMID:28231341), RNF145 is recruited to HMGCR via Insig-1/2 through its sterol-sensing domain YLYF motif, and its RING finger (Cys-537) catalyzes HMGCR ubiquitination and proteasomal degradation in parallel with gp78 and Hrd1 (PMID:30543180, PMID:29374057). RNF145 also ubiquitinates SCAP on cytoplasmic lysines required for COPII binding, thereby blocking SCAP–SREBP-2 transport to the Golgi and suppressing cholesterol biosynthetic gene expression (PMID:29068315). Beyond sterols, RNF145 senses membrane lipid saturation: in unsaturated membranes it ubiquitinates and degrades the lipid hydrolase ADIPOR2, whereas saturated fatty acid enrichment triggers RNF145 auto-ubiquitination and self-degradation, stabilizing ADIPOR2 to restore lipid balance; this dual sensing is coupled to the membrane-anchored E2 UBE2J2, with which RNF145 forms a reconstituted ERAD ubiquitination cascade whose activity responds to cholesterol-dependent oligomerization and lipid packing (PMID:35993436, PMID:41068091).

1. 2017 High

   Establishing that RNF145 is an LXR-regulated ER E3 ligase answered the question of how the cholesterol-sensing transcription factor LXR feeds back on ER protein quality control, linking nuclear receptor signaling to ubiquitin-dependent degradation.

   Evidence Transcriptional analysis, luciferase LXR-element reporter, in vitro ubiquitination assay, and Lxrα/β knockout mice and macrophages

   PMID:28231341

   Open questions at the time

   • Physiological substrates of RNF145 were not identified in this study
   • Mechanism linking LXR-induced RNF145 to specific cholesterol homeostatic outcomes was unknown
2. 2017 High

   Demonstrating that RNF145 ubiquitinates SCAP on COPII-binding lysines revealed a previously missing negative-feedback arm by which LXR activation suppresses SREBP-2 processing independently of oxysterol-mediated SCAP retention.

   Evidence Adenoviral overexpression and genetic deletion of RNF145 in mouse liver, ubiquitination site mapping, SCAP-COPII binding assay

   PMID:29068315

   Open questions at the time

   • Whether SCAP ubiquitination leads to ERAD or only blocks COPII sorting was not resolved
   • Relative contribution of RNF145 versus other E3s for SCAP regulation in vivo was unclear
3. 2018 High

   Identification of RNF145 as a sterol-responsive HMGCR E3 ligase acting via Insig scaffolding resolved the long-standing question of which additional E3s besides gp78 mediate sterol-accelerated HMGCR degradation, and defined the catalytic requirements (YLYF motif for Insig binding, Cys-537 for RING activity).

   Evidence CRISPR genome-wide screens, site-directed mutagenesis, Co-IP with Insig-1/2, epistasis with gp78 and Hrd1 double knockouts in multiple cell types

   PMID:29374057 PMID:30543180

   Open questions at the time

   • Structural basis of the RNF145–Insig–HMGCR ternary complex is unknown
   • How RNF145, gp78, and Hrd1 are differentially regulated to partition HMGCR degradation was not determined
4. 2020 Medium

   C. elegans work showed that the RNF145 ortholog's subcellular redistribution from cis-Golgi to trans-Golgi network developmentally releases SREBP inhibition, establishing that dynamic localization — not just expression — controls RNF145 pathway output.

   Evidence C. elegans epistasis, live imaging of rnf-145 localization, suppressor genetics, and fatty acid profiling

   PMID:33370778

   Open questions at the time

   • Whether mammalian RNF145 undergoes analogous Golgi redistribution has not been tested
   • The eas-1/GOLT1B-dependent shuttling mechanism has no demonstrated mammalian counterpart
5. 2022 High

   Discovery that RNF145 senses membrane lipid saturation — ubiquitinating ADIPOR2 in unsaturated membranes and auto-ubiquitinating itself in saturated membranes — extended its role from sterol sensing to a broader lipid composition sensor that prevents lipotoxicity.

   Evidence Quantitative proteomics comparing saturated versus unsaturated fatty acid conditions, RNF145 KO cells, ubiquitination assays, lipid composition analysis

   PMID:35993436

   Open questions at the time

   • Structural mechanism by which membrane saturation switches RNF145 from substrate to self-ubiquitination is unknown
   • Whether sterol and fatty acid sensing operate through the same or distinct domains was not resolved
6. 2025 High

   Reconstitution of the RNF145–UBE2J2 ERAD cascade with purified components demonstrated that cholesterol alters RNF145 oligomerization and that UBE2J2 senses lipid packing, providing the first biochemically defined mechanism for how membrane composition is transduced into E3 ligase activity.

   Evidence Fully reconstituted in vitro ubiquitination system with purified ERAD factors and defined membrane compositions

   PMID:41068091

   Open questions at the time

   • High-resolution structure of RNF145 oligomers in different lipid environments is lacking
   • Full substrate repertoire of the RNF145–UBE2J2 cascade beyond squalene monooxygenase and HMGCR is undefined
7. 2026 Medium

   Identification of PCDH9 as an RNF145 substrate in hepatocellular carcinoma expanded the known substrate range beyond lipid-homeostatic targets to cell adhesion molecules relevant to cancer metastasis.

   Evidence Co-IP, ubiquitination assay, and transwell/wound-healing assays in RNF145-knockdown HCC cells

   PMID:41613811

   Open questions at the time

   • Single-lab finding; independent replication is needed
   • Whether PCDH9 ubiquitination depends on membrane lipid status or Insig scaffolding is unknown
   • In vivo metastasis validation was not reported

• Open question: how the sterol-sensing domain, fatty acid sensing, and RING domain are structurally coupled to switch RNF145 between distinct substrates and self-degradation, and what the full in vivo substrate landscape is across tissues.
• No high-resolution structure of RNF145 exists
• Tissue-specific substrate profiling has not been performed
• Relative physiological contributions of RNF145 versus gp78/Hrd1 across metabolic states are unresolved