{"gene":"RNF145","run_date":"2026-06-10T06:43:37","timeline":{"discoveries":[{"year":2018,"finding":"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.","method":"CRISPR/Cas9 genome-wide screens with sterol-sensitive endogenous HMGCR reporter; genetic epistasis; Co-IP; loss-of-function (double KO)","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — unbiased genome-wide screen, epistasis, reciprocal Co-IP, replicated across two independent 2018 papers from different labs","pmids":["30543180"],"is_preprint":false},{"year":2018,"finding":"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.","method":"shRNA knockdown screen; Co-IP; active-site mutagenesis (YLYF motif, Cys-537); cell-based HMGCR degradation assay in CHO cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis of catalytic residue and substrate-binding motif with functional readout, replicated finding from independent lab","pmids":["29374057"],"is_preprint":false},{"year":2017,"finding":"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.","method":"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","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (gain-of-function in vivo, loss-of-function KD and KO, Co-IP, mutagenesis) in a single rigorous study","pmids":["29068315"],"is_preprint":false},{"year":2017,"finding":"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).","method":"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","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (transcriptomic, KO mouse, in vitro ligase assay, localization), single lab","pmids":["28231341"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Quantitative proteomics (comparing cells fed saturated vs. unsaturated FAs); Co-IP; ubiquitination assays; genetic loss-of-function; lipotoxicity assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic proteomics plus Co-IP, ubiquitination assays, and functional lipotoxicity readout with multiple orthogonal methods","pmids":["35993436"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Reconstituted in vitro ubiquitination system with purified ERAD factors; lipid-composition-defined liposomes; activity assays with E1, UBE2J2, RNF145","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — biochemical reconstitution with purified components and lipid manipulation, single lab but multiple rigorous in vitro methods","pmids":["41068091"],"is_preprint":false},{"year":2020,"finding":"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.","method":"C. elegans genetic epistasis; live imaging of Golgi localization; loss-of-function mutants with glial size phenotype; lipid supplementation experiments","journal":"PLoS biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis and live imaging in C. elegans ortholog, single lab, multiple methods","pmids":["33370778"],"is_preprint":false},{"year":2026,"finding":"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.","method":"Co-IP; ubiquitination assay with K63-linkage-specific analysis; ectopic expression of RNF145 in HEK293T cells with IFN/cytokine readout","journal":"Journal of reproductive immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP and ubiquitination assay with linkage specificity, single lab, single study","pmids":["42224957"],"is_preprint":false},{"year":2026,"finding":"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.","method":"Protein co-immunoprecipitation; Western blot for PCDH9 levels; transwell migration/invasion assays with RNF145 knockdown","journal":"Oncology research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP and knockdown phenotype, single lab, single study","pmids":["41613811"],"is_preprint":false}],"current_model":"RNF145 is a sterol- and lipid-responsive ER-resident RING-domain E3 ubiquitin ligase that, upon recruitment via Insig proteins under sterol-replete conditions, ubiquitinates HMGCR (promoting its proteasomal degradation) and SCAP (inhibiting SREBP-2 processing); it is transcriptionally induced by LXR activation, undergoes auto-ubiquitination and degradation when membranes are enriched in saturated fatty acids (thereby stabilizing the lipid hydrolase ADIPOR2 to restore membrane homeostasis), and its E3 activity requires Cys-537 in the RING domain and the YLYF sterol-sensing motif for Insig binding; it also cooperates with the E2 UBE2J2 in the broader ERAD ubiquitination cascade and has additional reported substrates including IRF3 (K63-linked ubiquitination) and PCDH9."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2017,"claim":"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","pmids":["29068315","28231341"],"confidence":"High","gaps":["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"]},{"year":2018,"claim":"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","pmids":["30543180","29374057"],"confidence":"High","gaps":["redundancy with gp78 and Hrd1 complicates assigning relative in vivo contributions","no structure of the RNF145–Insig–HMGCR assembly"]},{"year":2022,"claim":"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","pmids":["35993436"],"confidence":"High","gaps":["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"]},{"year":2025,"claim":"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","pmids":["41068091"],"confidence":"High","gaps":["how cholesterol-driven oligomerization is structurally coupled to RING activity unknown","relative use of UBE2J2 versus other E2s for different substrates not resolved"]},{"year":2020,"claim":"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","pmids":["33370778"],"confidence":"Medium","gaps":["cis-to-trans Golgi shuttling mechanism for the mammalian protein not demonstrated","glial growth role not tested in mammals"]},{"year":2026,"claim":"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)","pmids":["42224957","41613811"],"confidence":"Medium","gaps":["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"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2,4,5]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[4,5]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,2,3]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,2,4]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,5]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[4,5]}],"complexes":[],"partners":["INSIG1","INSIG2","HMGCR","SCAP","ADIPOR2","UBE2J2","IRF3","PCDH9"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96MT1","full_name":"RING finger protein 145","aliases":[],"length_aa":663,"mass_kda":75.6,"function":"E3 ubiquitin ligase that catalyzes the direct transfer of ubiquitin from E2 ubiquitin-conjugating enzyme to a specific substrate. In response to bacterial infection, negatively regulates the phagocyte oxidative burst by controlling the turnover of the NADPH oxidase complex subunits. Promotes monoubiquitination of CYBA and 'Lys-48'-linked polyubiquitination and degradation of CYBB NADPH oxidase catalytic subunits, both essential for the generation of antimicrobial reactive oxygen species. Involved in the maintenance of cholesterol homeostasis. In response to high sterol concentrations ubiquitinates HMGCR, a rate-limiting enzyme in cholesterol biosynthesis, and targets it for degradation. The interaction with INSIG1 is required for this function. In addition, triggers ubiquitination of SCAP, likely inhibiting its transport to the Golgi apparatus and the subsequent processing/maturation of SREBPF2, ultimately down-regulating cholesterol biosynthesis","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q96MT1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RNF145","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":383,"dependency_fraction":0.0026109660574412533},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RNF145","total_profiled":1310},"omim":[{"mim_id":"620640","title":"RING FINGER PROTEIN 145; RNF145","url":"https://www.omim.org/entry/620640"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RNF145"},"hgnc":{"alias_symbol":["FLJ31951"],"prev_symbol":[]},"alphafold":{"accession":"Q96MT1","domains":[{"cath_id":"-","chopping":"73-223","consensus_level":"high","plddt":86.2444,"start":73,"end":223},{"cath_id":"-","chopping":"227-440","consensus_level":"medium","plddt":89.0622,"start":227,"end":440},{"cath_id":"3.30.40.10","chopping":"523-568","consensus_level":"high","plddt":86.7041,"start":523,"end":568}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96MT1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96MT1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96MT1-F1-predicted_aligned_error_v6.png","plddt_mean":78.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RNF145","jax_strain_url":"https://www.jax.org/strain/search?query=RNF145"},"sequence":{"accession":"Q96MT1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96MT1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96MT1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96MT1"}},"corpus_meta":[{"pmid":"30543180","id":"PMC_30543180","title":"The sterol-responsive RNF145 E3 ubiquitin ligase mediates the degradation of HMG-CoA reductase together with gp78 and Hrd1.","date":"2018","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/30543180","citation_count":92,"is_preprint":false},{"pmid":"29374057","id":"PMC_29374057","title":"Ring finger protein 145 (RNF145) is a ubiquitin ligase for sterol-induced degradation of HMG-CoA reductase.","date":"2018","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29374057","citation_count":64,"is_preprint":false},{"pmid":"29068315","id":"PMC_29068315","title":"Inhibition of cholesterol biosynthesis through RNF145-dependent ubiquitination of SCAP.","date":"2017","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/29068315","citation_count":51,"is_preprint":false},{"pmid":"35047011","id":"PMC_35047011","title":"Using Machine Learning to Predict Obesity Based on Genome-Wide and Epigenome-Wide Gene-Gene and Gene-Diet 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medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35365168","citation_count":20,"is_preprint":false},{"pmid":"28139377","id":"PMC_28139377","title":"CPT1A methylation is associated with plasma adiponectin.","date":"2016","source":"Nutrition, metabolism, and cardiovascular diseases : NMCD","url":"https://pubmed.ncbi.nlm.nih.gov/28139377","citation_count":19,"is_preprint":false},{"pmid":"28059166","id":"PMC_28059166","title":"Mean Platelet Volume and Arterial Stiffness - Clinical Relationship and Common Genetic Variability.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28059166","citation_count":18,"is_preprint":false},{"pmid":"36797040","id":"PMC_36797040","title":"Identification of new risk loci shared across systemic vasculitides points towards potential target genes for drug repurposing.","date":"2023","source":"Annals of the rheumatic 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markers.","date":"2024","source":"Comparative biochemistry and physiology. Part D, Genomics & proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/39612541","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15021,"output_tokens":2697,"usd":0.042759,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9822,"output_tokens":3241,"usd":0.065068,"stage2_stop_reason":"end_turn"},"total_usd":0.107827,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"CRISPR/Cas9 genome-wide screens with sterol-sensitive endogenous HMGCR reporter; genetic epistasis; Co-IP; loss-of-function (double KO)\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — unbiased genome-wide screen, epistasis, reciprocal Co-IP, replicated across two independent 2018 papers from different labs\",\n      \"pmids\": [\"30543180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"shRNA knockdown screen; Co-IP; active-site mutagenesis (YLYF motif, Cys-537); cell-based HMGCR degradation assay in CHO cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis of catalytic residue and substrate-binding motif with functional readout, replicated finding from independent lab\",\n      \"pmids\": [\"29374057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (gain-of-function in vivo, loss-of-function KD and KO, Co-IP, mutagenesis) in a single rigorous study\",\n      \"pmids\": [\"29068315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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).\",\n      \"method\": \"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\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (transcriptomic, KO mouse, in vitro ligase assay, localization), single lab\",\n      \"pmids\": [\"28231341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Quantitative proteomics (comparing cells fed saturated vs. unsaturated FAs); Co-IP; ubiquitination assays; genetic loss-of-function; lipotoxicity assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic proteomics plus Co-IP, ubiquitination assays, and functional lipotoxicity readout with multiple orthogonal methods\",\n      \"pmids\": [\"35993436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Reconstituted in vitro ubiquitination system with purified ERAD factors; lipid-composition-defined liposomes; activity assays with E1, UBE2J2, RNF145\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — biochemical reconstitution with purified components and lipid manipulation, single lab but multiple rigorous in vitro methods\",\n      \"pmids\": [\"41068091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"C. elegans genetic epistasis; live imaging of Golgi localization; loss-of-function mutants with glial size phenotype; lipid supplementation experiments\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis and live imaging in C. elegans ortholog, single lab, multiple methods\",\n      \"pmids\": [\"33370778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP; ubiquitination assay with K63-linkage-specific analysis; ectopic expression of RNF145 in HEK293T cells with IFN/cytokine readout\",\n      \"journal\": \"Journal of reproductive immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP and ubiquitination assay with linkage specificity, single lab, single study\",\n      \"pmids\": [\"42224957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"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.\",\n      \"method\": \"Protein co-immunoprecipitation; Western blot for PCDH9 levels; transwell migration/invasion assays with RNF145 knockdown\",\n      \"journal\": \"Oncology research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP and knockdown phenotype, single lab, single study\",\n      \"pmids\": [\"41613811\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RNF145 is a sterol- and lipid-responsive ER-resident RING-domain E3 ubiquitin ligase that, upon recruitment via Insig proteins under sterol-replete conditions, ubiquitinates HMGCR (promoting its proteasomal degradation) and SCAP (inhibiting SREBP-2 processing); it is transcriptionally induced by LXR activation, undergoes auto-ubiquitination and degradation when membranes are enriched in saturated fatty acids (thereby stabilizing the lipid hydrolase ADIPOR2 to restore membrane homeostasis), and its E3 activity requires Cys-537 in the RING domain and the YLYF sterol-sensing motif for Insig binding; it also cooperates with the E2 UBE2J2 in the broader ERAD ubiquitination cascade and has additional reported substrates including IRF3 (K63-linked ubiquitination) and PCDH9.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RNF145 is a sterol- and lipid-responsive ER-resident RING-domain E3 ubiquitin ligase that integrates membrane lipid status with control of cholesterol homeostasis [#0, #4]. 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 [#0]. 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 [#1]. 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 [#2, #3]. 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 [#4]. 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 [#5]. Additional substrate relationships reported in the corpus include K63-linked ubiquitination of IRF3 augmenting type I interferon signaling [#7] and degradation of PCDH9 in hepatocellular carcinoma cells [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2017,\n      \"claim\": \"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.\",\n      \"evidence\": \"Adenoviral gain-of-function in mouse liver, KO mice, Co-IP, SCAP ubiquitination-site mutagenesis, SREBP-2 processing Westerns; plus LXR-element reporter, LXR\\u03b1/\\u03b2 KO cells, in vitro ligase assay and ER co-localization\",\n      \"pmids\": [\"29068315\", \"28231341\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"30543180\", \"29374057\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"redundancy with gp78 and Hrd1 complicates assigning relative in vivo contributions\", \"no structure of the RNF145\\u2013Insig\\u2013HMGCR assembly\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"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.\",\n      \"evidence\": \"Quantitative proteomics comparing saturated vs unsaturated FA feeding, Co-IP, ubiquitination assays, genetic loss-of-function and lipotoxicity readouts\",\n      \"pmids\": [\"35993436\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"evidence\": \"Reconstituted in vitro ubiquitination with purified E1, UBE2J2 and RNF145 on lipid-composition-defined liposomes\",\n      \"pmids\": [\"41068091\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"how cholesterol-driven oligomerization is structurally coupled to RING activity unknown\", \"relative use of UBE2J2 versus other E2s for different substrates not resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"C. elegans genetic epistasis, live Golgi imaging, loss-of-function glial-size phenotypes and lipid supplementation\",\n      \"pmids\": [\"33370778\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"cis-to-trans Golgi shuttling mechanism for the mammalian protein not demonstrated\", \"glial growth role not tested in mammals\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"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.\",\n      \"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)\",\n      \"pmids\": [\"42224957\", \"41613811\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0061630\", \"supporting_discovery_ids\": [0, 1, 2, 3, 4, 5]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2, 4, 5]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 2, 4]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"INSIG1\", \"INSIG2\", \"HMGCR\", \"SCAP\", \"ADIPOR2\", \"UBE2J2\", \"IRF3\", \"PCDH9\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}