Affinage

RNF145

RING finger protein 145 · UniProt Q96MT1

Length
663 aa
Mass
75.6 kDa
Annotated
2026-06-10
25 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RNF145 is a sterol- and lipid-responsive ER-resident RING-domain E3 ubiquitin ligase that integrates membrane lipid status with control of cholesterol homeostasis (PMID:30543180, PMID:35993436). Under sterol-replete conditions it is recruited via Insig-1/Insig-2 to ubiquitinate HMG-CoA reductase (HMGCR), driving its proteasomal degradation in parallel with gp78, with Hrd1 partially compensating when both are absent (PMID:30543180). Insig binding requires the YLYF tetrapeptide in the sterol-sensing domain, and catalytic activity depends on Cys-537 in the RING finger; loss of either abolishes substrate degradation (PMID:29374057). RNF145 is transcriptionally induced by Liver X Receptors through an LXR response element in its promoter, and it additionally ubiquitinates SCAP on cytoplasmic-loop lysines required for COPII binding, restraining SREBP-2 processing and lowering cholesterol biosynthetic gene expression and plasma cholesterol in vivo (PMID:29068315, PMID:28231341). Beyond sterol sensing, RNF145 monitors membrane lipid saturation: in unsaturated membranes it degrades the lipid hydrolase ADIPOR2, whereas saturated-fatty-acid enrichment triggers RNF145 auto-ubiquitination and self-degradation, stabilizing ADIPOR2 to restore lipid homeostasis and prevent lipotoxicity (PMID:35993436). Reconstitution with purified components shows RNF145 cooperates with the membrane-anchored, lipid-packing-sensing E2 UBE2J2, senses cholesterol through changes in its own oligomerization, and ubiquitinates squalene monooxygenase as well as itself (PMID:41068091). Additional substrate relationships reported in the corpus include K63-linked ubiquitination of IRF3 augmenting type I interferon signaling (PMID:42224957) and degradation of PCDH9 in hepatocellular carcinoma cells (PMID:41613811).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2017 High

    Establishing how RNF145 enters the sterol regulatory circuit: it was unknown what links LXR signaling to SREBP control, and this showed RNF145 is an LXR-induced ER ligase that ubiquitinates SCAP to restrain SREBP-2 processing and lower cholesterol.

    Evidence Adenoviral gain-of-function in mouse liver, KO mice, Co-IP, SCAP ubiquitination-site mutagenesis, SREBP-2 processing Westerns; plus LXR-element reporter, LXRα/β KO cells, in vitro ligase assay and ER co-localization

    PMID:28231341 PMID:29068315

    Open questions at the time
    • RNF145 silencing in HepG2/HeLa did not impair SREBP processing, leaving cell-type dependence of the SCAP axis unresolved
    • structural basis of SCAP-loop recognition not defined
  2. 2018 High

    Defining a second substrate axis and the catalytic requirements: it was unclear whether RNF145 acts on HMGCR and through what residues, and this established Insig-dependent recruitment driving HMGCR degradation via the YLYF motif and RING Cys-537.

    Evidence Genome-wide CRISPR screens with a sterol-sensitive HMGCR reporter, genetic epistasis and double KO, reciprocal Co-IP, and YLYF/Cys-537 mutagenesis with cell-based degradation assays

    PMID:29374057 PMID:30543180

    Open questions at the time
    • redundancy with gp78 and Hrd1 complicates assigning relative in vivo contributions
    • no structure of the RNF145–Insig–HMGCR assembly
  3. 2022 High

    Extending RNF145 from sterol sensing to membrane fluidity control: it was unknown how cells couple lipid saturation to remodeling enzymes, and this showed RNF145 degrades ADIPOR2 in unsaturated membranes but auto-degrades under saturated-FA stress to stabilize ADIPOR2.

    Evidence Quantitative proteomics comparing saturated vs unsaturated FA feeding, Co-IP, ubiquitination assays, genetic loss-of-function and lipotoxicity readouts

    PMID:35993436

    Open questions at the time
    • the physical lipid feature sensed by RNF145 itself not pinned to a structural element
    • in vivo relevance of the ADIPOR2 axis to whole-organism lipotoxicity not addressed
  4. 2025 High

    Reconstituting the minimal enzymatic system: it was unresolved whether RNF145's lipid sensing is intrinsic and which E2 it uses, and purified-component assays showed cooperation with the packing-sensing E2 UBE2J2 and cholesterol-dependent RNF145 oligomerization controlling squalene monooxygenase ubiquitination.

    Evidence Reconstituted in vitro ubiquitination with purified E1, UBE2J2 and RNF145 on lipid-composition-defined liposomes

    PMID:41068091

    Open questions at the time
    • how cholesterol-driven oligomerization is structurally coupled to RING activity unknown
    • relative use of UBE2J2 versus other E2s for different substrates not resolved
  5. 2020 Medium

    Placing the pathway in a developmental context: the C. elegans ortholog rnf-145 acts in the cis-Golgi to inhibit SBP-1/SREBP and restrict glial growth, with GOLT1B/eas-1 relocating it to release inhibition, linking the ligase to PUFA output.

    Evidence C. elegans genetic epistasis, live Golgi imaging, loss-of-function glial-size phenotypes and lipid supplementation

    PMID:33370778

    Open questions at the time
    • cis-to-trans Golgi shuttling mechanism for the mammalian protein not demonstrated
    • glial growth role not tested in mammals
  6. 2026 Medium

    Probing non-sterol substrate relationships: RNF145 was reported to K63-ubiquitinate IRF3 to augment type I interferon signaling and to degrade PCDH9 to drive hepatocellular carcinoma migration, expanding its substrate repertoire beyond lipid metabolism.

    Evidence Co-IP with K63-linkage-specific ubiquitination assays and IFN/cytokine readouts in HEK293T (IRF3); Co-IP, PCDH9 Westerns and transwell assays with knockdown (PCDH9)

    PMID:41613811 PMID:42224957

    Open questions at the time
    • IRF3 finding rests on ectopic expression in a single cell line without endogenous validation
    • PCDH9 link is a single Co-IP plus knockdown phenotype, not independently confirmed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RNF145's distinct sensing inputs (Insig/sterol, cholesterol-driven oligomerization, membrane packing via UBE2J2) are integrated to select among substrates (HMGCR, SCAP, ADIPOR2, squalene monooxygenase, itself) remains unresolved.
  • no structural model of the RNF145 membrane-embedded sensing module
  • substrate selection logic across conditions not mapped
  • physiological hierarchy of its lipid-metabolic versus reported immune/oncogenic roles undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0140299 molecular sensor activity 2
Localization
GO:0005783 endoplasmic reticulum 3 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-392499 Metabolism of proteins 2 R-HSA-8953897 Cellular responses to stimuli 2
Partners
ADIPOR2HMGCRINSIG1INSIG2IRF3PCDH9SCAPUBE2J2

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2018 RNF145 is a sterol-responsive ER-resident E3 ubiquitin ligase that mediates sterol-accelerated degradation of HMG-CoA reductase (HMGCR). Under sterol-replete conditions, RNF145 is recruited to HMGCR via Insig proteins, promoting HMGCR ubiquitination and proteasome-mediated degradation. RNF145 acts independently of, but in parallel with, gp78; in the absence of both, Hrd1 (a third UBE2G2-dependent E3 ligase) partially compensates. CRISPR/Cas9 genome-wide screens with sterol-sensitive endogenous HMGCR reporter; genetic epistasis; Co-IP; loss-of-function (double KO) eLife High 30543180
2018 RNF145 interacts with Insig-1 and Insig-2 and ubiquitinates HMGCR in response to elevated sterols. The tetrapeptide sequence YLYF in the sterol-sensing domain is essential for RNF145 binding to Insigs, and Cys-537 in the RING finger domain is essential for E3 ubiquitin ligase activity; substitution of either abolishes RNF145-mediated HMGCR degradation. shRNA knockdown screen; Co-IP; active-site mutagenesis (YLYF motif, Cys-537); cell-based HMGCR degradation assay in CHO cells The Journal of biological chemistry High 29374057
2017 RNF145 is an LXR-induced ER-resident E3 ubiquitin ligase that triggers ubiquitination of SCAP on lysine residues within the cytoplasmic loop required for COPII binding, potentially inhibiting SCAP transport to the Golgi and subsequent SREBP-2 processing. RNF145 expression inhibits cholesterol biosynthetic gene expression and reduces plasma cholesterol in mice. Adenoviral transduction of RNF145 into mouse liver; shRNA-mediated knockdown; genetic deletion (KO mice); Co-IP; mutagenesis of SCAP ubiquitination sites; Western blot for SREBP-2 processing eLife High 29068315
2017 RNF145 is transcriptionally regulated by Liver X Receptors (LXRs) via a functional LXR response element in its proximal promoter, in human and mouse cells and in vivo. RNF145 is localized to the ER and possesses intrinsic E3 ubiquitin ligase activity. Silencing of RNF145 in HepG2 or HeLa cells does NOT impair SREBP1/2 processing or sterol-responsive gene expression in these cell lines (negative result). Global transcriptional analysis; LXR-element reporter/mutation; LXRα/β knockout mouse macrophages/fibroblasts; in vitro E3 ligase activity assay; ER co-localization imaging; siRNA knockdown + SREBP processing assay PloS one High 28231341
2022 RNF145 senses membrane lipid saturation and regulates membrane fluidity by ubiquitinating and degrading the lipid hydrolase ADIPOR2. In unsaturated lipid membranes, stable RNF145 promotes lipid-sensitive interaction with and degradation of ADIPOR2. When membranes become enriched in saturated fatty acids, RNF145 undergoes auto-ubiquitination and is itself degraded, thereby stabilizing ADIPOR2, whose hydrolase activity restores lipid homeostasis and prevents lipotoxicity. Quantitative proteomics (comparing cells fed saturated vs. unsaturated FAs); Co-IP; ubiquitination assays; genetic loss-of-function; lipotoxicity assays The EMBO journal High 35993436
2025 In a reconstituted in vitro ERAD system, RNF145 cooperates with the membrane-anchored E2 UBE2J2, which senses lipid packing; loosely packed membranes inactivate UBE2J2, reducing RNF145-directed ubiquitination. RNF145 itself senses cholesterol by altering its oligomerization and activity. RNF145 targets both itself and the substrate squalene monooxygenase for ubiquitination in conjunction with UBE2J2. Reconstituted in vitro ubiquitination system with purified ERAD factors; lipid-composition-defined liposomes; activity assays with E1, UBE2J2, RNF145 Nature communications High 41068091
2020 In C. elegans, the RNF145 ortholog rnf-145 acts in the cis-Golgi network to inhibit activation of the SREBP transcription factor sbp-1, restricting glial cell growth. A cis-Golgi protein eas-1/GOLT1B shuttles rnf-145 from cis- to trans-Golgi at the adult stage to release this inhibition and stop glial growth. Long-chain PUFAs (especially EPA) are downstream products of the eas-1–rnf-145–sbp-1 pathway. C. elegans genetic epistasis; live imaging of Golgi localization; loss-of-function mutants with glial size phenotype; lipid supplementation experiments PLoS biology Medium 33370778
2026 RNF145 interacts with IRF3 and induces K63-linked polyubiquitination of IRF3, augmenting IRF3-mediated signaling and promoting production of type I interferons and inflammatory cytokines in human embryonic kidney 293T cells. Co-IP; ubiquitination assay with K63-linkage-specific analysis; ectopic expression of RNF145 in HEK293T cells with IFN/cytokine readout Journal of reproductive immunology Medium 42224957
2026 RNF145 promotes hepatocellular carcinoma cell migration and invasion by ubiquitinating and degrading protocadherin 9 (PCDH9); knockdown of RNF145 abolishes the migratory and invasive capacity of HCC cells. Protein co-immunoprecipitation; Western blot for PCDH9 levels; transwell migration/invasion assays with RNF145 knockdown Oncology research Low 41613811

Source papers

Stage 0 corpus · 25 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 The sterol-responsive RNF145 E3 ubiquitin ligase mediates the degradation of HMG-CoA reductase together with gp78 and Hrd1. eLife 92 30543180
2018 Ring finger protein 145 (RNF145) is a ubiquitin ligase for sterol-induced degradation of HMG-CoA reductase. The Journal of biological chemistry 64 29374057
2017 Inhibition of cholesterol biosynthesis through RNF145-dependent ubiquitination of SCAP. eLife 51 29068315
2022 Using Machine Learning to Predict Obesity Based on Genome-Wide and Epigenome-Wide Gene-Gene and Gene-Diet Interactions. Frontiers in genetics 37 35047011
2017 Identification of the ER-resident E3 ubiquitin ligase RNF145 as a novel LXR-regulated gene. PloS one 27 28231341
2022 Regulation of membrane fluidity by RNF145-triggered degradation of the lipid hydrolase ADIPOR2. The EMBO journal 23 35993436
2022 CircZDBF2 up-regulates RNF145 by ceRNA model and recruits CEBPB to accelerate oral squamous cell carcinoma progression via NFκB signaling pathway. Journal of translational medicine 20 35365168
2016 CPT1A methylation is associated with plasma adiponectin. Nutrition, metabolism, and cardiovascular diseases : NMCD 19 28139377
2017 Mean Platelet Volume and Arterial Stiffness - Clinical Relationship and Common Genetic Variability. Scientific reports 18 28059166
2023 Identification of new risk loci shared across systemic vasculitides points towards potential target genes for drug repurposing. Annals of the rheumatic diseases 16 36797040
2014 Identification of clinically important chromosomal aberrations in acute myeloid leukemia by array-based comparative genomic hybridization. Leukemia & lymphoma 12 24446873
2021 Transcriptional Profiles Reveal Deregulation of Lipid Metabolism and Inflammatory Pathways in Neurons Exposed to Palmitic Acid. Molecular neurobiology 10 34155583
2020 Regulation of glial size by eicosapentaenoic acid through a novel Golgi apparatus mechanism. PLoS biology 7 33370778
2025 Molecular Markers of Occult Lymph Node Metastasis in Head and Neck Squamous Cell Carcinoma (HNSCC) Patients. Frontiers in bioscience (Landmark edition) 5 40018925
2023 Promoter-Specific Variants in NeuroD1 and H3K4me3 Coincident Regions and Clinical Outcomes of Small Cell Lung Cancer. Journal of Korean medical science 5 37987107
2021 Genetic variation of RNF145 gene and blood lipid levels in Xinjiang population, China. Scientific reports 5 33727652
2025 UBE2J2 sensitizes the ERAD ubiquitination cascade to changes in membrane lipid saturation. Nature communications 2 41068091
2024 Palmdelphin Inhibits Ovarian Cancer Cell Stem Specification via Downregulating Ring Finger Protein 145. Critical reviews in eukaryotic gene expression 2 39180204
2026 Single-cell transcriptome-wide Mendelian randomization and colocalization reveal cell-specific mechanisms in systemic lupus erythematosus. Rheumatology (Oxford, England) 0 41233983
2026 RNF145 Promotes Hepatocellular Carcinoma Metastasis through Ubiquitination and Degradation of PCDH9. Oncology research 0 41613811
2026 Marine-Derived Chitooligosaccharide Attenuates Obesity and Metabolic Syndrome in Bama Pigs Through LXR-Mediated Cholesterol Metabolism and Gut Microbiota Modulation. Nutrients 0 42075046
2026 RNF145 promotes inflammation in recurrent spontaneous abortion through inducing the K63-linked polyubiquitination of IRF3. Journal of reproductive immunology 0 42224957
2025 In Silico Analysis of the Role of Estrogen Signaling in the Expression of Metabolic Genes in Breast Cancer. Asian Pacific journal of cancer prevention : APJCP 0 41459856
2024 Multi-omics study of sex in greater amberjack (Seriola dumerili): Identifying related genes, analyzing sex-biased expression, and developing sex-specific markers. Comparative biochemistry and physiology. Part D, Genomics & proteomics 0 39612541
2023 As a matter of fat: Emerging roles of lipid-sensitive E3 ubiquitin ligases. BioEssays : news and reviews in molecular, cellular and developmental biology 0 37890275

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