{"gene":"RNF139","run_date":"2026-06-10T06:43:37","timeline":{"discoveries":[{"year":1998,"finding":"TRC8 (RNF139) encodes a 664-amino acid multi-membrane spanning ER protein with similarity to patched, containing a putative sterol-sensing domain and a RING finger motif. The hereditary t(3;8) translocation disrupts TRC8 within its sterol-sensing domain, and an acquired TRC8 mutation was identified in sporadic renal carcinomas.","method":"Molecular cloning, sequence analysis, breakpoint characterization","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — initial molecular characterization with sequence and domain analysis plus translocation mapping, single lab but multiple orthogonal methods","pmids":["9689122"],"is_preprint":false},{"year":2002,"finding":"TRC8 protein localizes to the endoplasmic reticulum, encodes a RING-H2 finger with in vitro ubiquitin ligase activity, physically interacts with DVhl (Drosophila VHL) as shown by GST-pulldown and co-immunoprecipitation, and both DTrc8 and DVhl loss-of-function produce an identical ventral midline defect in Drosophila. DTrc8 also physically interacts with CSN-5/JAB1.","method":"GST-pulldown, co-immunoprecipitation, in vitro ubiquitin ligase assay, subcellular fractionation/localization, Drosophila genetic epistasis","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro ubiquitin ligase assay, reciprocal pulldown/Co-IP, genetic epistasis, subcellular localization, multiple orthogonal methods in one study","pmids":["12032852"],"is_preprint":false},{"year":2005,"finding":"TRC8-induced growth suppression in Drosophila is dependent on CSN5/JAB1 and CSN6 (COP9 signalosome subunits): haploinsufficiency of CSN5 or specific point mutations (T100I) relieved DTrc8-dependent growth suppression, consistent with yeast two-hybrid interaction strengths. DTrc8 overexpression elevated levels of CSN5, CSN7, and the CSN holocomplex.","method":"Drosophila genetic epistasis, yeast two-hybrid, immunoblot","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with multiple alleles, yeast two-hybrid, single lab","pmids":["15735686"],"is_preprint":false},{"year":2006,"finding":"TRC8 causes G2/M arrest, decreased DNA synthesis, increased apoptosis, and tumor suppression in a nude mouse model, all dependent on the RING-H2 ubiquitin ligase domain. TRC8 represses SREBP target genes (cholesterol/fatty acid biosynthesis), and expression of activated SREBP-1a partially restores growth of TRC8-inhibited cells.","method":"RING domain mutagenesis, flow cytometry, BrdU incorporation, nude mouse xenograft, gene expression analysis, epistasis via SREBP-1a rescue","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — RING mutagenesis ablates phenotype, multiple orthogonal readouts (cell cycle, apoptosis, in vivo tumor), SREBP epistasis, single lab","pmids":["17016439"],"is_preprint":false},{"year":2009,"finding":"TRC8 is required for US2-mediated MHC class I ubiquitination and dislocation from the ER. TRC8 forms a multiprotein ER complex containing MHC I, US2, and signal peptide peptidase (SPP). Depletion of TRC8 prevents MHC I ubiquitination and dislocation and restores cell surface MHC I.","method":"siRNA library functional screen, co-immunoprecipitation (complex formation), flow cytometry (cell surface MHC I), immunoblot for ubiquitination","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional siRNA screen identifying TRC8, complex characterized by Co-IP, cell surface and ubiquitination readouts, mechanistically coherent with replicated ERAD role","pmids":["19720873"],"is_preprint":false},{"year":2009,"finding":"TRC8 binds both SREBP-2 and SCAP, forming a TRC8·SREBP-2·SCAP complex at the ER that blocks SCAP interaction with Sec24 (a COPII component), thereby preventing ER-to-Golgi transport of SREBP-2 and reducing SREBP-2 cleavage/activation. This inhibition of SREBP-2 processing is independent of TRC8 E3 ligase activity. TRC8 undergoes auto-ubiquitination and is destabilized by the proteasome; its stability is increased under sterol-depleted conditions.","method":"Co-immunoprecipitation, RING domain mutagenesis, proteasome inhibitor treatment, lipoprotein depletion, SREBP-2 cleavage/processing assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — Co-IP of ternary complex, mutagenesis distinguishing ligase-dependent vs independent function, multiple orthogonal assays, single lab","pmids":["19706601"],"is_preprint":false},{"year":2010,"finding":"TRC8 protein levels are sterol-responsive; TRC8 binds INSIG and stimulates INSIG ubiquitylation. TRC8 overexpression destabilizes precursor forms of SREBP-1 and SREBP-2 in a RING-dependent, proteasome-dependent manner. TRC8 physically interacts with eIF3 subunits (eIF3f and eIF3h) as confirmed by co-immunoprecipitation, and TRC8 overexpression suppresses polysome profiles and generates ubiquitylated proteins in eIF3 immunoprecipitates.","method":"Co-immunoprecipitation, RING domain mutagenesis, polysome profiling, immunoblot, Drosophila genetic interaction","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, mutagenesis, polysome profiling, Drosophila genetics, single lab with multiple orthogonal methods","pmids":["20068067"],"is_preprint":false},{"year":2011,"finding":"TRC8 and gp78 are both RING-finger E3 ubiquitin ligases that cooperate in sterol-induced ubiquitination and proteasomal degradation of HMG-CoA reductase. Both Insig-1 and Insig-2 bind TRC8. TRC8 knockdown inhibits sterol-induced reductase ubiquitination and degradation by 50-60%; combined knockdown of gp78 and TRC8 produces >90% inhibition. Knockdown of gp78 increases TRC8 and Insig-1 protein levels three- to fourfold.","method":"RNAi knockdown, co-immunoprecipitation, ubiquitination assay, pulse-chase degradation assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal RNAi, Co-IP binding, quantitative ubiquitination and degradation assays; independently extends prior mechanistic work on the same substrate","pmids":["22143767"],"is_preprint":false},{"year":2012,"finding":"TRC8 targets heme oxygenase-1 (HO-1) for ubiquitination and proteasomal degradation at the ER. Ectopic TRC8 suppresses HO-1-induced cancer cell growth and migration/invasion; HO-1 depletion reduces the tumorigenic and invasive capacities caused by TRC8 knockdown, placing HO-1 downstream of TRC8.","method":"Co-immunoprecipitation, ubiquitination assay, cell viability/invasion assays, siRNA epistasis","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, genetic epistasis (HO-1 depletion rescues TRC8-KD phenotype), multiple orthogonal methods in single lab","pmids":["22689053"],"is_preprint":false},{"year":2016,"finding":"TRC8 is required for proteasomal degradation of the immature (uncleaved) HCV core protein. SPP cleavage of immature core prevents TRC8-mediated degradation; in SPP-knockout or SPP-inhibitor-treated cells, the uncleaved immature core is rapidly degraded via TRC8-dependent ubiquitin-proteasome pathway. Loss of both SPP and TRC8 causes ER stress.","method":"SPP knockout/inhibitor, TRC8 siRNA knockdown, ubiquitination assay, ER stress markers, immunoblot","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO and pharmacological inhibition combined with TRC8 knockdown, mechanistic epistasis, multiple orthogonal methods, single lab","pmids":["27142248"],"is_preprint":false},{"year":2016,"finding":"TRC8 interacts through its transmembrane region with misfolded hERG potassium channel and mediates its ubiquitin-proteasome degradation together with E2-conjugating enzyme Ube2g2. The co-chaperone Bag1 shifts hERG degradation from CHIP-dependent to TRC8-dependent machinery. TRC8 also mediates degradation of the misfolded hERG-G601S disease mutant, and pharmacological stabilization of mutant structure prevents TRC8-mediated degradation.","method":"siRNA screen, co-immunoprecipitation (transmembrane interaction), electrophysiology (functional expression), pharmacological stabilization, ubiquitination assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — siRNA functional screen, Co-IP mapping domain of interaction, electrophysiology functional readout, disease mutant rescue experiment, single lab","pmids":["27998983"],"is_preprint":false},{"year":2018,"finding":"TRC8 and MARCH6 are both ER-resident E3 ligases required for proteasome-mediated degradation of the misfolded soluble reporter mCherry-CL1, which is routed via the ER membrane in a substrate-hydrophobicity-dependent manner. Complete stabilization of mCherry-CL1 requires double knockout of both MARCH6 and TRC8. TRC8 and MARCH6 also associate with signal peptide peptidase (SPP) and facilitate degradation of the tail-anchored protein heme oxygenase-1 (HO-1) following intramembrane proteolysis.","method":"Forward genetic screen (haploid human cells), CRISPR double knockout, quantitative mass spectrometry (turnover), co-immunoprecipitation with SPP","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — forward genetic screen, CRISPR double KO, quantitative proteomics, Co-IP, multiple orthogonal methods in single lab","pmids":["29519897"],"is_preprint":false},{"year":2018,"finding":"INSIG1 coordinates with TRC8 to promote HIV-1 Gag protein degradation through the lysosome pathway (distinct from HMGCR degradation which uses gp78/AMFR and the proteasome). This degradation occurs at intracellular membrane sites including ER and endosomes.","method":"Pseudovirus production assay, protein overexpression and gene knockout, pathway inhibitors (proteasome vs lysosome), co-localization","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional knockouts and pathway dissection, single lab, single study","pmids":["30563842"],"is_preprint":false},{"year":2020,"finding":"DEPTOR promotes TRC8 auto-ubiquitination and degradation by the ubiquitin-proteasome system in chondrocytes. Loss of DEPTOR leads to TRC8 accumulation, excessive ER stress, and chondrocyte apoptosis. Adenovirus-mediated TRC8 overexpression in chondrocytes exacerbates ER stress.","method":"Proteomics, co-immunoprecipitation, DEPTOR knockout mouse model, adenoviral overexpression, ER stress markers","journal":"Journal of bone and mineral research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, in vivo KO model, adenoviral overexpression, proteomics, single lab","pmids":["32916025"],"is_preprint":false},{"year":2024,"finding":"HCMV pUS2 co-opts TRC8 to degrade the ER-resident protein LMAN2L. pUS2 expression is both necessary and sufficient for LMAN2L downregulation in a TRC8-dependent manner. LMAN2L loss impairs trafficking of integrin alpha-6 (ITGA6) to the plasma membrane.","method":"Co-immunoprecipitation, siRNA/CRISPR knockdown, proteomic plasma membrane profiling, viral expression assays","journal":"The Journal of general virology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — TRC8 dependency established by knockdown, pUS2 necessity/sufficiency tested, single lab, single study","pmids":["38687323"],"is_preprint":false},{"year":2025,"finding":"RNF139 (TRC8) functions as an E3 ligase downstream of the membrane-anchored E2 enzyme UBE2J2 in the ERAD ubiquitination cascade. In reconstituted systems with purified factors, UBE2J2 activity (which is modulated by membrane lipid packing) directs ubiquitin transfer to RNF139 as well as to squalene monooxygenase substrate.","method":"Reconstituted in vitro ubiquitination assay with purified ERAD components, proteoliposome systems","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — reconstituted in vitro system with purified components is Tier 1 quality, but preprint, single lab, no mutagenesis confirmation","pmids":["bio_10.1101_2025.07.22.666085"],"is_preprint":true},{"year":2025,"finding":"NR4A3 transcriptionally activates RNF139 via KLF2 and KLF4. RNF139 directly interacts with ATF6 and mediates its ubiquitination at lysine 152, promoting ATF6 degradation and inhibiting ER stress in bladder cancer cells.","method":"Co-immunoprecipitation, ubiquitination assay with site-specific mutagenesis (K152), cycloheximide chase, transcriptional reporter assays, xenograft","journal":"Pathology, research and practice","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP, ubiquitination with site-specific mutation, single lab, single study","pmids":["41406921"],"is_preprint":false}],"current_model":"RNF139/TRC8 is an ER-resident multi-membrane spanning RING-H2 E3 ubiquitin ligase that senses sterols via its sterol-sensing domain and functions as a central node in ER-associated degradation (ERAD): it directly ubiquitinates HMG-CoA reductase (cooperating with Insig-1/2 and gp78), suppresses SREBP processing by forming a TRC8·SREBP-2·SCAP complex that blocks COPII-dependent ER-to-Golgi transport, ubiquitinates heme oxygenase-1 (HO-1) and ATF6 for proteasomal degradation, mediates quality-control degradation of misfolded proteins including hERG and mCherry-CL1 (with MARCH6 and SPP), is co-opted by HCMV US2 to degrade MHC class I and LMAN2L, acts downstream of the E2 enzyme UBE2J2 in a lipid-sensing ERAD cascade, and its own stability is regulated by auto-ubiquitination and by DEPTOR-promoted self-degradation."},"narrative":{"mechanistic_narrative":"RNF139 (TRC8) is an ER-resident, multi-membrane-spanning RING-H2 E3 ubiquitin ligase that couples sterol sensing to protein turnover and serves as a central node in ER-associated degradation (ERAD) [PMID:9689122, PMID:12032852]. Through a putative sterol-sensing domain it acts as a lipid-responsive regulator of cholesterol homeostasis: it cooperates with gp78 and binds Insig-1/2 to drive sterol-induced ubiquitination and proteasomal degradation of HMG-CoA reductase [PMID:22143767], and it suppresses SREBP processing by assembling a TRC8·SREBP-2·SCAP complex that blocks SCAP–Sec24 (COPII) interaction and thereby prevents ER-to-Golgi transport and cleavage of SREBP-2, a function independent of its ligase activity [PMID:19706601]. Its RING-H2 ligase activity drives degradation of additional ER substrates, including heme oxygenase-1, ATF6 (ubiquitinated at K152), and the misfolded hERG channel, and operates in quality-control degradation of soluble misfolded reporters redundantly with MARCH6 and in concert with signal peptide peptidase [PMID:22689053, PMID:41406921, PMID:27998983, PMID:29519897]. RNF139 receives ubiquitin from the membrane-anchored E2 enzyme UBE2J2 in a lipid-packing-sensitive ERAD cascade [PMID:bio_10.1101_2025.07.22.666085], and its own abundance is sterol-responsive and controlled by auto-ubiquitination and DEPTOR-promoted self-degradation [PMID:19706601, PMID:32916025]. The ligase is co-opted by HCMV US2 to dislocate and degrade MHC class I and LMAN2L from the ER [PMID:19720873, PMID:38687323], and via its RING domain it enforces cell-cycle arrest, apoptosis, and tumor suppression, with its disruption linked to hereditary t(3;8) renal carcinoma [PMID:9689122, PMID:17016439].","teleology":[{"year":1998,"claim":"Established the molecular identity of TRC8/RNF139 as an ER protein bearing both a sterol-sensing domain and a RING finger, and linked it to renal cancer, framing it as a candidate sterol-responsive regulator and tumor suppressor.","evidence":"Molecular cloning, sequence/domain analysis, and t(3;8) breakpoint characterization","pmids":["9689122"],"confidence":"Medium","gaps":["No enzymatic activity demonstrated","No substrates identified","Functional consequence of sterol-sensing domain untested"]},{"year":2002,"claim":"Demonstrated that TRC8 is an active ER-localized ubiquitin ligase with in vivo genetic partners, moving it from a sequence-predicted RING protein to a functional E3.","evidence":"In vitro ubiquitin ligase assay, GST-pulldown/Co-IP with DVhl and CSN-5/JAB1, and Drosophila genetic epistasis","pmids":["12032852"],"confidence":"High","gaps":["Physiological ubiquitination substrate not defined","Relevance of VHL/CSN5 interactions to mammalian function unclear"]},{"year":2006,"claim":"Tied TRC8 ligase activity to a defined cellular outcome by showing RING-dependent cell-cycle arrest, apoptosis, and tumor suppression operating through repression of SREBP target genes.","evidence":"RING mutagenesis, cell-cycle/apoptosis assays, nude mouse xenograft, and SREBP-1a rescue epistasis","pmids":["17016439"],"confidence":"High","gaps":["Direct molecular link between TRC8 and SREBP not yet defined","Mechanism of SREBP-target repression unresolved"]},{"year":2009,"claim":"Resolved how TRC8 controls SREBP-2: it sequesters SREBP-2·SCAP and blocks COPII-dependent ER exit, a ligase-independent mechanism, while clarifying that TRC8 stability is itself sterol- and proteasome-regulated.","evidence":"Co-IP of ternary complex, RING mutagenesis distinguishing ligase-independent function, proteasome inhibition, and SREBP-2 processing assays","pmids":["19706601"],"confidence":"High","gaps":["Stoichiometry and structure of the TRC8·SREBP-2·SCAP complex unknown","How sterol status switches TRC8 stability not mechanistically defined"]},{"year":2009,"claim":"Established TRC8 as a host ERAD factor hijacked by viruses, required for US2-mediated MHC I ubiquitination and dislocation within an ER complex containing SPP.","evidence":"siRNA functional screen, Co-IP of MHC I/US2/SPP complex, flow cytometry for surface MHC I, ubiquitination immunoblot","pmids":["19720873"],"confidence":"High","gaps":["Direct vs indirect recognition of MHC I substrate unresolved","Role of SPP catalytic activity in the dislocation step undefined"]},{"year":2011,"claim":"Defined TRC8 as a partially redundant ERAD ligase for HMG-CoA reductase acting with gp78 and Insig, quantifying its contribution to sterol-regulated reductase degradation.","evidence":"Reciprocal RNAi, Co-IP with Insig-1/2, quantitative ubiquitination and pulse-chase degradation assays","pmids":["22143767"],"confidence":"High","gaps":["E2 partner for reductase ubiquitination by TRC8 not specified here","Basis for functional split between TRC8 and gp78 unclear"]},{"year":2012,"claim":"Expanded the TRC8 substrate repertoire to heme oxygenase-1, linking TRC8-mediated HO-1 degradation to suppression of cancer cell growth and invasion.","evidence":"Co-IP, ubiquitination assay, viability/invasion assays, siRNA epistasis placing HO-1 downstream of TRC8","pmids":["22689053"],"confidence":"High","gaps":["Role of intramembrane processing in HO-1 degradation not yet addressed","Recognition determinants on HO-1 undefined"]},{"year":2016,"claim":"Demonstrated TRC8 functions in misfolded-protein quality control, degrading the disease-associated misfolded hERG channel via its transmembrane region with Ube2g2, with chaperone choice (Bag1) routing substrates to TRC8.","evidence":"siRNA screen, transmembrane-domain Co-IP, electrophysiology, pharmacological stabilization, ubiquitination assay","pmids":["27998983"],"confidence":"High","gaps":["How TRC8 discriminates misfolded from native transmembrane substrates unknown","Generality beyond hERG untested in this study"]},{"year":2016,"claim":"Showed intramembrane proteolysis gates TRC8 substrate access, with SPP cleavage protecting HCV core from TRC8-dependent degradation and combined SPP/TRC8 loss triggering ER stress.","evidence":"SPP knockout/inhibitor combined with TRC8 siRNA, ubiquitination assay, ER stress markers","pmids":["27142248"],"confidence":"High","gaps":["Direct interaction between TRC8 and immature core not fully mapped","Coupling between SPP cleavage and TRC8 engagement mechanistically undefined"]},{"year":2018,"claim":"Generalized TRC8's quality-control role: it acts redundantly with MARCH6 and alongside SPP to degrade hydrophobic misfolded substrates (mCherry-CL1) routed through the ER membrane.","evidence":"Haploid forward genetic screen, CRISPR double knockout, quantitative turnover proteomics, Co-IP with SPP","pmids":["29519897"],"confidence":"High","gaps":["Substrate features that partition between TRC8 and MARCH6 not defined","Structural basis of SPP–ligase coupling unknown"]},{"year":2018,"claim":"Implicated TRC8 in restriction of HIV-1 Gag, revealing a lysosomal degradation route distinct from its proteasomal handling of HMGCR.","evidence":"Pseudovirus assays, knockouts, proteasome vs lysosome inhibitors, co-localization","pmids":["30563842"],"confidence":"Medium","gaps":["Single study, single lab","Mechanism directing substrates to lysosome vs proteasome unresolved"]},{"year":2020,"claim":"Identified DEPTOR as a regulator of TRC8 abundance, showing DEPTOR promotes TRC8 auto-ubiquitination/degradation to limit ER stress and chondrocyte apoptosis.","evidence":"Proteomics, Co-IP, DEPTOR knockout mouse, adenoviral TRC8 overexpression, ER stress markers","pmids":["32916025"],"confidence":"Medium","gaps":["Whether DEPTOR acts directly on TRC8 or via another factor unclear","Single study, single lab"]},{"year":2024,"claim":"Added LMAN2L as an HCMV pUS2-directed TRC8 substrate, connecting TRC8-mediated ER degradation to downstream plasma-membrane trafficking of integrin alpha-6.","evidence":"Co-IP, siRNA/CRISPR knockdown, plasma-membrane proteomics, viral expression assays","pmids":["38687323"],"confidence":"Medium","gaps":["Single study, single lab","Direct vs adaptor-mediated recognition of LMAN2L undefined"]},{"year":2025,"claim":"Placed RNF139 within a defined ERAD enzymatic cascade as a ligase receiving ubiquitin from the membrane E2 UBE2J2 in a lipid-packing-sensitive manner, providing a biochemical link between membrane lipid state and ubiquitin transfer.","evidence":"Reconstituted in vitro ubiquitination with purified factors and proteoliposomes (preprint)","pmids":["bio_10.1101_2025.07.22.666085"],"confidence":"Medium","gaps":["Preprint, single lab, no mutagenesis confirmation","Physiological relevance of UBE2J2–RNF139 pairing in cells not shown"]},{"year":2025,"claim":"Demonstrated transcriptional and substrate-level regulation of the ER stress axis by RNF139, which is activated via NR4A3/KLF2/KLF4 and ubiquitinates ATF6 at K152 to limit ER stress in bladder cancer.","evidence":"Co-IP, site-specific (K152) ubiquitination mutagenesis, cycloheximide chase, transcriptional reporters, xenograft","pmids":["41406921"],"confidence":"Medium","gaps":["Single study, single lab","Generality of ATF6 regulation beyond bladder cancer untested"]},{"year":null,"claim":"How RNF139 selects and discriminates among its diverse substrates, and how its sterol-sensing domain mechanistically transduces lipid status into substrate engagement and ligase activity, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the sterol-sensing domain or substrate-binding interface","Determinants partitioning substrates between TRC8 and partner ligases (gp78, MARCH6) undefined","Mechanism coupling sterol sensing to ligase activity vs ligase-independent SREBP sequestration unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[1,7,16]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,7,8,16]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[1,7]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[0,6]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[5]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,1,5,8,11]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[12]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[4,7,8,11,15]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[3,5,7]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[13,16]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,14]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,9,12]}],"complexes":["TRC8·SREBP-2·SCAP complex","TRC8·MHC I·US2·SPP ER dislocation complex"],"partners":["SCAP","SREBP-2","INSIG1","INSIG2","AMFR","MARCH6","UBE2J2","ATF6"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8WU17","full_name":"E3 ubiquitin-protein ligase RNF139","aliases":["RING finger protein 139","RING-type E3 ubiquitin transferase RNF139","Translocation in renal carcinoma on chromosome 8 protein"],"length_aa":664,"mass_kda":76.0,"function":"E3-ubiquitin ligase; acts as a negative regulator of cell proliferation through mechanisms involving G2/M arrest and cell death (PubMed:10500182, PubMed:12032852, PubMed:17016439). Required for MHC class I ubiquitination in cells expressing the cytomegalovirus protein US2 before dislocation from the endoplasmic reticulum (ER) (PubMed:19720873). Affects SREBP processing by hindering the SREBP-SCAP complex translocation from the ER to the Golgi, thereby reducing SREBF2 target gene expression (PubMed:19706601, PubMed:20068067). Involved in the sterol-accelerated degradation of HMGCR (PubMed:22143767, PubMed:23223569). This is achieved through binding of RNF139 to INSIG1 and/or INSIG2 at the ER membrane (PubMed:22143767). In addition, interaction of RNF139 with AUP1 facilitates interaction of RNF139 with ubiquitin-conjugating enzyme UBE2G2 and ubiquitin ligase AMFR, leading to ubiquitination of HMGCR (PubMed:23223569). The ubiquitinated HMGCR is then released from the ER into the cytosol for subsequent destruction (PubMed:22143767, PubMed:23223569). Required for INSIG1 ubiquitination (PubMed:20068067). May be required for EIF3 complex ubiquitination (PubMed:20068067)","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q8WU17/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RNF139","classification":"Not Classified","n_dependent_lines":35,"n_total_lines":1208,"dependency_fraction":0.028973509933774833},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RNF139","total_profiled":1310},"omim":[{"mim_id":"620640","title":"RING FINGER PROTEIN 145; RNF145","url":"https://www.omim.org/entry/620640"},{"mim_id":"603046","title":"RING FINGER PROTEIN 139; RNF139","url":"https://www.omim.org/entry/603046"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"bone marrow","ntpm":88.0}],"url":"https://www.proteinatlas.org/search/RNF139"},"hgnc":{"alias_symbol":["TRC8","RCA1","HRCA1"],"prev_symbol":[]},"alphafold":{"accession":"Q8WU17","domains":[{"cath_id":"-","chopping":"16-105_126-231","consensus_level":"medium","plddt":85.197,"start":16,"end":231},{"cath_id":"-","chopping":"239-402_427-446","consensus_level":"high","plddt":88.8897,"start":239,"end":446},{"cath_id":"3.30.40.10","chopping":"533-590","consensus_level":"medium","plddt":85.8655,"start":533,"end":590},{"cath_id":"1.20.58","chopping":"456-532","consensus_level":"medium","plddt":87.4796,"start":456,"end":532}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WU17","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WU17-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WU17-F1-predicted_aligned_error_v6.png","plddt_mean":79.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RNF139","jax_strain_url":"https://www.jax.org/strain/search?query=RNF139"},"sequence":{"accession":"Q8WU17","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8WU17.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8WU17/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WU17"}},"corpus_meta":[{"pmid":"22143767","id":"PMC_22143767","title":"Sterol-induced degradation of HMG CoA reductase depends on interplay of two Insigs and two ubiquitin ligases, gp78 and Trc8.","date":"2011","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/22143767","citation_count":139,"is_preprint":false},{"pmid":"9689122","id":"PMC_9689122","title":"The hereditary renal cell carcinoma 3;8 translocation fuses FHIT to a patched-related gene, TRC8.","date":"1998","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/9689122","citation_count":128,"is_preprint":false},{"pmid":"19720873","id":"PMC_19720873","title":"The TRC8 E3 ligase ubiquitinates MHC class I molecules before dislocation from the ER.","date":"2009","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/19720873","citation_count":123,"is_preprint":false},{"pmid":"9000053","id":"PMC_9000053","title":"Control of G1 in the 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The hereditary t(3;8) translocation disrupts TRC8 within its sterol-sensing domain, and an acquired TRC8 mutation was identified in sporadic renal carcinomas.\",\n      \"method\": \"Molecular cloning, sequence analysis, breakpoint characterization\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — initial molecular characterization with sequence and domain analysis plus translocation mapping, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"9689122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"TRC8 protein localizes to the endoplasmic reticulum, encodes a RING-H2 finger with in vitro ubiquitin ligase activity, physically interacts with DVhl (Drosophila VHL) as shown by GST-pulldown and co-immunoprecipitation, and both DTrc8 and DVhl loss-of-function produce an identical ventral midline defect in Drosophila. DTrc8 also physically interacts with CSN-5/JAB1.\",\n      \"method\": \"GST-pulldown, co-immunoprecipitation, in vitro ubiquitin ligase assay, subcellular fractionation/localization, Drosophila genetic epistasis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro ubiquitin ligase assay, reciprocal pulldown/Co-IP, genetic epistasis, subcellular localization, multiple orthogonal methods in one study\",\n      \"pmids\": [\"12032852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TRC8-induced growth suppression in Drosophila is dependent on CSN5/JAB1 and CSN6 (COP9 signalosome subunits): haploinsufficiency of CSN5 or specific point mutations (T100I) relieved DTrc8-dependent growth suppression, consistent with yeast two-hybrid interaction strengths. DTrc8 overexpression elevated levels of CSN5, CSN7, and the CSN holocomplex.\",\n      \"method\": \"Drosophila genetic epistasis, yeast two-hybrid, immunoblot\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with multiple alleles, yeast two-hybrid, single lab\",\n      \"pmids\": [\"15735686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"TRC8 causes G2/M arrest, decreased DNA synthesis, increased apoptosis, and tumor suppression in a nude mouse model, all dependent on the RING-H2 ubiquitin ligase domain. TRC8 represses SREBP target genes (cholesterol/fatty acid biosynthesis), and expression of activated SREBP-1a partially restores growth of TRC8-inhibited cells.\",\n      \"method\": \"RING domain mutagenesis, flow cytometry, BrdU incorporation, nude mouse xenograft, gene expression analysis, epistasis via SREBP-1a rescue\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — RING mutagenesis ablates phenotype, multiple orthogonal readouts (cell cycle, apoptosis, in vivo tumor), SREBP epistasis, single lab\",\n      \"pmids\": [\"17016439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"TRC8 is required for US2-mediated MHC class I ubiquitination and dislocation from the ER. TRC8 forms a multiprotein ER complex containing MHC I, US2, and signal peptide peptidase (SPP). Depletion of TRC8 prevents MHC I ubiquitination and dislocation and restores cell surface MHC I.\",\n      \"method\": \"siRNA library functional screen, co-immunoprecipitation (complex formation), flow cytometry (cell surface MHC I), immunoblot for ubiquitination\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional siRNA screen identifying TRC8, complex characterized by Co-IP, cell surface and ubiquitination readouts, mechanistically coherent with replicated ERAD role\",\n      \"pmids\": [\"19720873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"TRC8 binds both SREBP-2 and SCAP, forming a TRC8·SREBP-2·SCAP complex at the ER that blocks SCAP interaction with Sec24 (a COPII component), thereby preventing ER-to-Golgi transport of SREBP-2 and reducing SREBP-2 cleavage/activation. This inhibition of SREBP-2 processing is independent of TRC8 E3 ligase activity. TRC8 undergoes auto-ubiquitination and is destabilized by the proteasome; its stability is increased under sterol-depleted conditions.\",\n      \"method\": \"Co-immunoprecipitation, RING domain mutagenesis, proteasome inhibitor treatment, lipoprotein depletion, SREBP-2 cleavage/processing assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — Co-IP of ternary complex, mutagenesis distinguishing ligase-dependent vs independent function, multiple orthogonal assays, single lab\",\n      \"pmids\": [\"19706601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TRC8 protein levels are sterol-responsive; TRC8 binds INSIG and stimulates INSIG ubiquitylation. TRC8 overexpression destabilizes precursor forms of SREBP-1 and SREBP-2 in a RING-dependent, proteasome-dependent manner. TRC8 physically interacts with eIF3 subunits (eIF3f and eIF3h) as confirmed by co-immunoprecipitation, and TRC8 overexpression suppresses polysome profiles and generates ubiquitylated proteins in eIF3 immunoprecipitates.\",\n      \"method\": \"Co-immunoprecipitation, RING domain mutagenesis, polysome profiling, immunoblot, Drosophila genetic interaction\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, mutagenesis, polysome profiling, Drosophila genetics, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"20068067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TRC8 and gp78 are both RING-finger E3 ubiquitin ligases that cooperate in sterol-induced ubiquitination and proteasomal degradation of HMG-CoA reductase. Both Insig-1 and Insig-2 bind TRC8. TRC8 knockdown inhibits sterol-induced reductase ubiquitination and degradation by 50-60%; combined knockdown of gp78 and TRC8 produces >90% inhibition. Knockdown of gp78 increases TRC8 and Insig-1 protein levels three- to fourfold.\",\n      \"method\": \"RNAi knockdown, co-immunoprecipitation, ubiquitination assay, pulse-chase degradation assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal RNAi, Co-IP binding, quantitative ubiquitination and degradation assays; independently extends prior mechanistic work on the same substrate\",\n      \"pmids\": [\"22143767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TRC8 targets heme oxygenase-1 (HO-1) for ubiquitination and proteasomal degradation at the ER. Ectopic TRC8 suppresses HO-1-induced cancer cell growth and migration/invasion; HO-1 depletion reduces the tumorigenic and invasive capacities caused by TRC8 knockdown, placing HO-1 downstream of TRC8.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, cell viability/invasion assays, siRNA epistasis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, genetic epistasis (HO-1 depletion rescues TRC8-KD phenotype), multiple orthogonal methods in single lab\",\n      \"pmids\": [\"22689053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TRC8 is required for proteasomal degradation of the immature (uncleaved) HCV core protein. SPP cleavage of immature core prevents TRC8-mediated degradation; in SPP-knockout or SPP-inhibitor-treated cells, the uncleaved immature core is rapidly degraded via TRC8-dependent ubiquitin-proteasome pathway. Loss of both SPP and TRC8 causes ER stress.\",\n      \"method\": \"SPP knockout/inhibitor, TRC8 siRNA knockdown, ubiquitination assay, ER stress markers, immunoblot\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO and pharmacological inhibition combined with TRC8 knockdown, mechanistic epistasis, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"27142248\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TRC8 interacts through its transmembrane region with misfolded hERG potassium channel and mediates its ubiquitin-proteasome degradation together with E2-conjugating enzyme Ube2g2. The co-chaperone Bag1 shifts hERG degradation from CHIP-dependent to TRC8-dependent machinery. TRC8 also mediates degradation of the misfolded hERG-G601S disease mutant, and pharmacological stabilization of mutant structure prevents TRC8-mediated degradation.\",\n      \"method\": \"siRNA screen, co-immunoprecipitation (transmembrane interaction), electrophysiology (functional expression), pharmacological stabilization, ubiquitination assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA functional screen, Co-IP mapping domain of interaction, electrophysiology functional readout, disease mutant rescue experiment, single lab\",\n      \"pmids\": [\"27998983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TRC8 and MARCH6 are both ER-resident E3 ligases required for proteasome-mediated degradation of the misfolded soluble reporter mCherry-CL1, which is routed via the ER membrane in a substrate-hydrophobicity-dependent manner. Complete stabilization of mCherry-CL1 requires double knockout of both MARCH6 and TRC8. TRC8 and MARCH6 also associate with signal peptide peptidase (SPP) and facilitate degradation of the tail-anchored protein heme oxygenase-1 (HO-1) following intramembrane proteolysis.\",\n      \"method\": \"Forward genetic screen (haploid human cells), CRISPR double knockout, quantitative mass spectrometry (turnover), co-immunoprecipitation with SPP\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — forward genetic screen, CRISPR double KO, quantitative proteomics, Co-IP, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"29519897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"INSIG1 coordinates with TRC8 to promote HIV-1 Gag protein degradation through the lysosome pathway (distinct from HMGCR degradation which uses gp78/AMFR and the proteasome). This degradation occurs at intracellular membrane sites including ER and endosomes.\",\n      \"method\": \"Pseudovirus production assay, protein overexpression and gene knockout, pathway inhibitors (proteasome vs lysosome), co-localization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional knockouts and pathway dissection, single lab, single study\",\n      \"pmids\": [\"30563842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DEPTOR promotes TRC8 auto-ubiquitination and degradation by the ubiquitin-proteasome system in chondrocytes. Loss of DEPTOR leads to TRC8 accumulation, excessive ER stress, and chondrocyte apoptosis. Adenovirus-mediated TRC8 overexpression in chondrocytes exacerbates ER stress.\",\n      \"method\": \"Proteomics, co-immunoprecipitation, DEPTOR knockout mouse model, adenoviral overexpression, ER stress markers\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, in vivo KO model, adenoviral overexpression, proteomics, single lab\",\n      \"pmids\": [\"32916025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HCMV pUS2 co-opts TRC8 to degrade the ER-resident protein LMAN2L. pUS2 expression is both necessary and sufficient for LMAN2L downregulation in a TRC8-dependent manner. LMAN2L loss impairs trafficking of integrin alpha-6 (ITGA6) to the plasma membrane.\",\n      \"method\": \"Co-immunoprecipitation, siRNA/CRISPR knockdown, proteomic plasma membrane profiling, viral expression assays\",\n      \"journal\": \"The Journal of general virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — TRC8 dependency established by knockdown, pUS2 necessity/sufficiency tested, single lab, single study\",\n      \"pmids\": [\"38687323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RNF139 (TRC8) functions as an E3 ligase downstream of the membrane-anchored E2 enzyme UBE2J2 in the ERAD ubiquitination cascade. In reconstituted systems with purified factors, UBE2J2 activity (which is modulated by membrane lipid packing) directs ubiquitin transfer to RNF139 as well as to squalene monooxygenase substrate.\",\n      \"method\": \"Reconstituted in vitro ubiquitination assay with purified ERAD components, proteoliposome systems\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — reconstituted in vitro system with purified components is Tier 1 quality, but preprint, single lab, no mutagenesis confirmation\",\n      \"pmids\": [\"bio_10.1101_2025.07.22.666085\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NR4A3 transcriptionally activates RNF139 via KLF2 and KLF4. RNF139 directly interacts with ATF6 and mediates its ubiquitination at lysine 152, promoting ATF6 degradation and inhibiting ER stress in bladder cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay with site-specific mutagenesis (K152), cycloheximide chase, transcriptional reporter assays, xenograft\",\n      \"journal\": \"Pathology, research and practice\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP, ubiquitination with site-specific mutation, single lab, single study\",\n      \"pmids\": [\"41406921\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RNF139/TRC8 is an ER-resident multi-membrane spanning RING-H2 E3 ubiquitin ligase that senses sterols via its sterol-sensing domain and functions as a central node in ER-associated degradation (ERAD): it directly ubiquitinates HMG-CoA reductase (cooperating with Insig-1/2 and gp78), suppresses SREBP processing by forming a TRC8·SREBP-2·SCAP complex that blocks COPII-dependent ER-to-Golgi transport, ubiquitinates heme oxygenase-1 (HO-1) and ATF6 for proteasomal degradation, mediates quality-control degradation of misfolded proteins including hERG and mCherry-CL1 (with MARCH6 and SPP), is co-opted by HCMV US2 to degrade MHC class I and LMAN2L, acts downstream of the E2 enzyme UBE2J2 in a lipid-sensing ERAD cascade, and its own stability is regulated by auto-ubiquitination and by DEPTOR-promoted self-degradation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RNF139 (TRC8) is an ER-resident, multi-membrane-spanning RING-H2 E3 ubiquitin ligase that couples sterol sensing to protein turnover and serves as a central node in ER-associated degradation (ERAD) [#0, #1]. Through a putative sterol-sensing domain it acts as a lipid-responsive regulator of cholesterol homeostasis: it cooperates with gp78 and binds Insig-1/2 to drive sterol-induced ubiquitination and proteasomal degradation of HMG-CoA reductase [#7], and it suppresses SREBP processing by assembling a TRC8\\u00b7SREBP-2\\u00b7SCAP complex that blocks SCAP\\u2013Sec24 (COPII) interaction and thereby prevents ER-to-Golgi transport and cleavage of SREBP-2, a function independent of its ligase activity [#5]. Its RING-H2 ligase activity drives degradation of additional ER substrates, including heme oxygenase-1, ATF6 (ubiquitinated at K152), and the misfolded hERG channel, and operates in quality-control degradation of soluble misfolded reporters redundantly with MARCH6 and in concert with signal peptide peptidase [#8, #16, #10, #11]. RNF139 receives ubiquitin from the membrane-anchored E2 enzyme UBE2J2 in a lipid-packing-sensitive ERAD cascade [#15], and its own abundance is sterol-responsive and controlled by auto-ubiquitination and DEPTOR-promoted self-degradation [#5, #13]. The ligase is co-opted by HCMV US2 to dislocate and degrade MHC class I and LMAN2L from the ER [#4, #14], and via its RING domain it enforces cell-cycle arrest, apoptosis, and tumor suppression, with its disruption linked to hereditary t(3;8) renal carcinoma [#0, #3].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established the molecular identity of TRC8/RNF139 as an ER protein bearing both a sterol-sensing domain and a RING finger, and linked it to renal cancer, framing it as a candidate sterol-responsive regulator and tumor suppressor.\",\n      \"evidence\": \"Molecular cloning, sequence/domain analysis, and t(3;8) breakpoint characterization\",\n      \"pmids\": [\"9689122\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No enzymatic activity demonstrated\", \"No substrates identified\", \"Functional consequence of sterol-sensing domain untested\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Demonstrated that TRC8 is an active ER-localized ubiquitin ligase with in vivo genetic partners, moving it from a sequence-predicted RING protein to a functional E3.\",\n      \"evidence\": \"In vitro ubiquitin ligase assay, GST-pulldown/Co-IP with DVhl and CSN-5/JAB1, and Drosophila genetic epistasis\",\n      \"pmids\": [\"12032852\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological ubiquitination substrate not defined\", \"Relevance of VHL/CSN5 interactions to mammalian function unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Tied TRC8 ligase activity to a defined cellular outcome by showing RING-dependent cell-cycle arrest, apoptosis, and tumor suppression operating through repression of SREBP target genes.\",\n      \"evidence\": \"RING mutagenesis, cell-cycle/apoptosis assays, nude mouse xenograft, and SREBP-1a rescue epistasis\",\n      \"pmids\": [\"17016439\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular link between TRC8 and SREBP not yet defined\", \"Mechanism of SREBP-target repression unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Resolved how TRC8 controls SREBP-2: it sequesters SREBP-2\\u00b7SCAP and blocks COPII-dependent ER exit, a ligase-independent mechanism, while clarifying that TRC8 stability is itself sterol- and proteasome-regulated.\",\n      \"evidence\": \"Co-IP of ternary complex, RING mutagenesis distinguishing ligase-independent function, proteasome inhibition, and SREBP-2 processing assays\",\n      \"pmids\": [\"19706601\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structure of the TRC8\\u00b7SREBP-2\\u00b7SCAP complex unknown\", \"How sterol status switches TRC8 stability not mechanistically defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Established TRC8 as a host ERAD factor hijacked by viruses, required for US2-mediated MHC I ubiquitination and dislocation within an ER complex containing SPP.\",\n      \"evidence\": \"siRNA functional screen, Co-IP of MHC I/US2/SPP complex, flow cytometry for surface MHC I, ubiquitination immunoblot\",\n      \"pmids\": [\"19720873\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect recognition of MHC I substrate unresolved\", \"Role of SPP catalytic activity in the dislocation step undefined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined TRC8 as a partially redundant ERAD ligase for HMG-CoA reductase acting with gp78 and Insig, quantifying its contribution to sterol-regulated reductase degradation.\",\n      \"evidence\": \"Reciprocal RNAi, Co-IP with Insig-1/2, quantitative ubiquitination and pulse-chase degradation assays\",\n      \"pmids\": [\"22143767\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E2 partner for reductase ubiquitination by TRC8 not specified here\", \"Basis for functional split between TRC8 and gp78 unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Expanded the TRC8 substrate repertoire to heme oxygenase-1, linking TRC8-mediated HO-1 degradation to suppression of cancer cell growth and invasion.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, viability/invasion assays, siRNA epistasis placing HO-1 downstream of TRC8\",\n      \"pmids\": [\"22689053\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Role of intramembrane processing in HO-1 degradation not yet addressed\", \"Recognition determinants on HO-1 undefined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated TRC8 functions in misfolded-protein quality control, degrading the disease-associated misfolded hERG channel via its transmembrane region with Ube2g2, with chaperone choice (Bag1) routing substrates to TRC8.\",\n      \"evidence\": \"siRNA screen, transmembrane-domain Co-IP, electrophysiology, pharmacological stabilization, ubiquitination assay\",\n      \"pmids\": [\"27998983\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TRC8 discriminates misfolded from native transmembrane substrates unknown\", \"Generality beyond hERG untested in this study\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed intramembrane proteolysis gates TRC8 substrate access, with SPP cleavage protecting HCV core from TRC8-dependent degradation and combined SPP/TRC8 loss triggering ER stress.\",\n      \"evidence\": \"SPP knockout/inhibitor combined with TRC8 siRNA, ubiquitination assay, ER stress markers\",\n      \"pmids\": [\"27142248\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct interaction between TRC8 and immature core not fully mapped\", \"Coupling between SPP cleavage and TRC8 engagement mechanistically undefined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Generalized TRC8's quality-control role: it acts redundantly with MARCH6 and alongside SPP to degrade hydrophobic misfolded substrates (mCherry-CL1) routed through the ER membrane.\",\n      \"evidence\": \"Haploid forward genetic screen, CRISPR double knockout, quantitative turnover proteomics, Co-IP with SPP\",\n      \"pmids\": [\"29519897\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate features that partition between TRC8 and MARCH6 not defined\", \"Structural basis of SPP\\u2013ligase coupling unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Implicated TRC8 in restriction of HIV-1 Gag, revealing a lysosomal degradation route distinct from its proteasomal handling of HMGCR.\",\n      \"evidence\": \"Pseudovirus assays, knockouts, proteasome vs lysosome inhibitors, co-localization\",\n      \"pmids\": [\"30563842\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single study, single lab\", \"Mechanism directing substrates to lysosome vs proteasome unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified DEPTOR as a regulator of TRC8 abundance, showing DEPTOR promotes TRC8 auto-ubiquitination/degradation to limit ER stress and chondrocyte apoptosis.\",\n      \"evidence\": \"Proteomics, Co-IP, DEPTOR knockout mouse, adenoviral TRC8 overexpression, ER stress markers\",\n      \"pmids\": [\"32916025\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether DEPTOR acts directly on TRC8 or via another factor unclear\", \"Single study, single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Added LMAN2L as an HCMV pUS2-directed TRC8 substrate, connecting TRC8-mediated ER degradation to downstream plasma-membrane trafficking of integrin alpha-6.\",\n      \"evidence\": \"Co-IP, siRNA/CRISPR knockdown, plasma-membrane proteomics, viral expression assays\",\n      \"pmids\": [\"38687323\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single study, single lab\", \"Direct vs adaptor-mediated recognition of LMAN2L undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed RNF139 within a defined ERAD enzymatic cascade as a ligase receiving ubiquitin from the membrane E2 UBE2J2 in a lipid-packing-sensitive manner, providing a biochemical link between membrane lipid state and ubiquitin transfer.\",\n      \"evidence\": \"Reconstituted in vitro ubiquitination with purified factors and proteoliposomes (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.07.22.666085\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, single lab, no mutagenesis confirmation\", \"Physiological relevance of UBE2J2\\u2013RNF139 pairing in cells not shown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated transcriptional and substrate-level regulation of the ER stress axis by RNF139, which is activated via NR4A3/KLF2/KLF4 and ubiquitinates ATF6 at K152 to limit ER stress in bladder cancer.\",\n      \"evidence\": \"Co-IP, site-specific (K152) ubiquitination mutagenesis, cycloheximide chase, transcriptional reporters, xenograft\",\n      \"pmids\": [\"41406921\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single study, single lab\", \"Generality of ATF6 regulation beyond bladder cancer untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RNF139 selects and discriminates among its diverse substrates, and how its sterol-sensing domain mechanistically transduces lipid status into substrate engagement and ligase activity, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the sterol-sensing domain or substrate-binding interface\", \"Determinants partitioning substrates between TRC8 and partner ligases (gp78, MARCH6) undefined\", \"Mechanism coupling sterol sensing to ligase activity vs ligase-independent SREBP sequestration unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [1, 7, 16]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 7, 8, 16]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [1, 7]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 1, 5, 8, 11]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [4, 7, 8, 11, 15]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [3, 5, 7]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [13, 16]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 14]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 9, 12]}\n    ],\n    \"complexes\": [\n      \"TRC8\\u00b7SREBP-2\\u00b7SCAP complex\",\n      \"TRC8\\u00b7MHC I\\u00b7US2\\u00b7SPP ER dislocation complex\"\n    ],\n    \"partners\": [\n      \"SCAP\",\n      \"SREBP-2\",\n      \"INSIG1\",\n      \"INSIG2\",\n      \"AMFR\",\n      \"MARCH6\",\n      \"UBE2J2\",\n      \"ATF6\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}