{"gene":"RNF115","run_date":"2026-06-10T06:43:37","timeline":{"discoveries":[{"year":2003,"finding":"Rabring7 (RNF115) specifically binds the GTP-bound form of Rab7 at its N-terminal portion, is recruited from cytosol to late endosomes/lysosomes by GTP-Rab7, and its overexpression causes perinuclear lysosomal aggregation and affects EGF degradation.","method":"GST pull-down, co-immunoprecipitation, CytoTrap yeast two-hybrid, live-cell imaging with LysoTracker","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal GST pulldown and Co-IP with functional localization and phenotypic readout, replicated in follow-up Methods paper (PMID:16473630)","pmids":["12972561","16473630"],"is_preprint":false},{"year":2007,"finding":"Rabring7 (RNF115) has E3 ubiquitin ligase activity, preferentially using Ubc4/Ubc5 as E2 partners; autoubiquitination and EGFR degradation-promoting activity require Cys-229 in the RING finger domain (C229S mutation abolishes activity).","method":"In vitro ubiquitination assay with recombinant E1/E2 proteins, RING domain point mutagenesis, EGFR degradation assay","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with mutagenesis, single lab, two orthogonal methods","pmids":["17462600"],"is_preprint":false},{"year":2008,"finding":"BCA2 (RNF115) undergoes autoubiquitination via its RING-H2 domain; the BZF zinc finger domain binds ubiquitin and ubiquitinated proteins; lysines K26/K32 in BZF are required for autoubiquitination; K232/K260 mutations near the RING domain increase autoubiquitination; BCA2 affects breast cancer cell migration.","method":"BacterioMatch two-hybrid screening, deletion/point mutagenesis, in vivo ubiquitination assay, cell migration assay","journal":"Molecular cancer research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — mutagenesis of active site residues with in vivo ubiquitination assay plus functional cell migration readout, single lab, multiple orthogonal methods","pmids":["18819927"],"is_preprint":false},{"year":2009,"finding":"BCA2 (RNF115) is a tetherin-interacting E3 ubiquitin ligase that, in tetherin-positive cells, restricts HIV-1 particle production by facilitating internalization of virions into CD63+ intracellular vesicles and promoting their lysosomal degradation.","method":"Co-immunoprecipitation (tetherin interaction), RNAi knockdown, virion release assay, immunofluorescence for CD63+ vesicle colocalization","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, RNAi loss-of-function with defined phenotype, subcellular localization with functional consequence; replicated in subsequent studies","pmids":["20019814"],"is_preprint":false},{"year":2012,"finding":"BCA2 (RNF115) binds hHR23a and 14-3-3sigma; hHR23a stabilizes BCA2 by inhibiting its autoubiquitination activity; phosphorylated BCA2 is stabilized by 14-3-3sigma via protein-protein interaction.","method":"Yeast two-hybrid, bacterial two-hybrid, in vitro binding with tagged proteins, in vivo autoubiquitination assay","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP confirmed binding and functional effect on autoubiquitination; single lab, two orthogonal methods","pmids":["22315970"],"is_preprint":false},{"year":2012,"finding":"Rabring7 (RNF115) binds MM-1 and c-Myc; monoubiquitinates MM-1 in the cytoplasm without degradation; ubiquitinates c-Myc in a Thr58-dependent manner; co-expression of Rabring7 and MM-1 leads to c-Myc degradation, requiring nuclear co-localization.","method":"Co-immunoprecipitation, in vivo ubiquitination assay, co-transfection/overexpression, knockdown of MM-1, immunofluorescence co-localization","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP plus ubiquitination assay plus KD rescue, single lab","pmids":["22844532"],"is_preprint":false},{"year":2013,"finding":"Rabring7 (RNF115) associates with EGFR through its ubiquitin-binding zinc finger domain; promotes EGFR ubiquitination and lysosomal degradation; functions downstream of c-Cbl (binding is reduced in c-Cbl-deficient cells or cells expressing Cbl-70Z); depletion retains EGFR in a late endocytic compartment; also regulates MET degradation and CXCR4 sorting; depletion destabilizes ESCRT-II and reduces multivesicular body formation.","method":"Co-immunoprecipitation, RNAi depletion, EGFR degradation assay, electron microscopy (MVB counting), receptor sorting assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, RNAi, EM, receptor degradation), genetic epistasis with c-Cbl, multiple receptor substrates tested","pmids":["23418353"],"is_preprint":false},{"year":2013,"finding":"BCA2 (RNF115) promotes ubiquitination and proteasomal degradation of p21Waf1/Cip1; directly interacts with p21; knockdown of BCA2 increases p21 protein stability and decreases ERα-positive breast cancer cell proliferation; partial rescue of growth arrest by p21 knockdown confirms the pathway.","method":"siRNA knockdown, co-immunoprecipitation, ubiquitination assay, cell proliferation assay, rescue experiment","journal":"Neoplasia","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct Co-IP, ubiquitination assay, genetic rescue (p21 KD), single lab, multiple orthogonal methods","pmids":["24027428"],"is_preprint":false},{"year":2017,"finding":"BCA2 (RNF115) acts as an E3 SUMO ligase for IκBα SUMOylation, enhancing sequestration of NF-κB components in the cytoplasm; this reduces NF-κB-dependent HIV-1 proviral transcription; BCA2 is induced by NF-κB-activating cytokines providing a negative feedback loop.","method":"SUMO ligase assay, NF-κB reporter assay, IκBα SUMOylation assay, HIV-1 transcription assay in CD4+ T cells","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — SUMOylation assay plus reporter assay plus functional HIV transcription readout, single lab","pmids":["28122985"],"is_preprint":false},{"year":2020,"finding":"RNF115 constitutively interacts with MAVS and induces K48-linked ubiquitination and proteasomal degradation of MAVS in uninfected cells; after HSV-1 infection, RNF115 associates with MITA/STING and catalyzes K63-linked ubiquitination to promote MITA aggregation and antiviral signaling; Rnf115-/- mice show increased MAVS and impaired MITA aggregation.","method":"Co-immunoprecipitation, ubiquitin chain-type-specific assays (K48/K63), Rnf115 knockout mice, viral infection assays (EMCV, HSV-1), western blotting for protein levels","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, chain-type-specific ubiquitination assays, KO mice with in vivo phenotype, two distinct substrates/viral contexts","pmids":["33139700"],"is_preprint":false},{"year":2020,"finding":"RNF115 interacts with STX17 (syntaxin 17) and enhances its stability, which is required for autophagosome-lysosome fusion; RNF115 deletion impairs autophagosome maturation and causes accumulation of autophagosomes.","method":"Co-immunoprecipitation, RNF115 gene knockout/depletion, autophagy flux assay, electron microscopy, in vitro/in vivo tumor models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP plus KO phenotype plus autophagy flux assay, single lab","pmids":["32980859"],"is_preprint":false},{"year":2020,"finding":"RNF115 mediates ubiquitination and degradation of p53, promoting lung adenocarcinoma cell proliferation; RNF115 disruption induces G1 phase arrest and reduces tumor growth in a xenograft model.","method":"Ubiquitination assay, RNF115 knockdown/disruption, flow cytometry cell cycle analysis, xenograft tumor model","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — ubiquitination assay and loss-of-function phenotype, single lab, limited mechanistic detail in abstract","pmids":["32553631"],"is_preprint":false},{"year":2021,"finding":"RNF115 mediates ubiquitination and proteasomal degradation of APC (adenomatous polyposis coli), activating the Wnt/β-catenin signaling pathway in lung adenocarcinoma cells.","method":"RNF115 knockdown/overexpression, ubiquitination assay, Wnt/β-catenin pathway reporter assay","journal":"Cancer & metabolism","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — ubiquitination assay with pathway readout, single lab, limited detail in abstract","pmids":["33509267"],"is_preprint":false},{"year":2022,"finding":"AKT1-phosphorylated RNF115 is chaperoned by 14-3-3 proteins to localize on the ER and Golgi apparatus, where it interacts with RAB1A and RAB13, catalyzing K11-linked ubiquitination at Lys49/Lys61 of RAB1A and Lys46/Lys58 of RAB13; this modification impairs GDI1 recruitment to these RAB proteins, blocking GDP-dissociation and impairing post-ER and post-Golgi TLR trafficking.","method":"Co-immunoprecipitation, in vitro ubiquitination assay with chain-type-specific analysis, site-directed mutagenesis (RAB1A/RAB13 lysine mutants), Rnf115 KO cells with reconstitution, TLR trafficking assay","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro ubiquitination with mutagenesis of specific lysines, KO rescue experiments, GDI1 recruitment assay as mechanistic readout, single lab but multiple orthogonal methods","pmids":["35343654"],"is_preprint":false},{"year":2022,"finding":"RNF115 is enriched on phagosomes of IFN-γ-activated macrophages; loss of RNF115 protein or its ligase activity enhances phagosomal maturation and increases cytokine responses to bacterial infection; RNF115 knockout mice show less tissue damage during S. aureus infection.","method":"Quantitative proteomics of phagosomes, RNF115 knockout cells and mice, phagosomal maturation assay, cytokine measurement, S. aureus infection model","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — quantitative proteomics plus KO with defined phenotype plus in vivo mouse model, multiple orthogonal methods","pmids":["36281581"],"is_preprint":false},{"year":2023,"finding":"RNF115 interacts with LC3B and downregulates LC3B protein levels and cellular autophagy; RNF115 deletion promotes autophagy and inhibits M1 macrophage activation via NF-κB and JNK pathways, protecting against acute liver injury.","method":"Co-immunoprecipitation (RNF115-LC3B), Rnf115 KO mice, autophagy flux assay, cytokine measurement, macrophage depletion experiment","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP plus KO mice with defined phenotype and macrophage depletion rescue, single lab","pmids":["38129372"],"is_preprint":false},{"year":2024,"finding":"RNF115 ubiquitinates and promotes degradation of CDK10 in thyroid carcinoma cells, thereby activating the Raf-1 pathway and enhancing cell cycle progression; CDK10 overexpression counteracts RNF115-mediated malignant phenotypes.","method":"Co-immunoprecipitation, ubiquitination assay, CDK10 overexpression rescue, in vitro and in vivo tumor models, Raf-1 pathway analysis","journal":"Cell biology and toxicology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — ubiquitination assay plus genetic rescue plus in vivo model, single lab","pmids":["38376606"],"is_preprint":false},{"year":2024,"finding":"RNF115 promotes K63-linked ubiquitination of STING/MITA and its Golgi localization/oligomerization; knockout or pharmacological inhibition of RNF115 by disulfiram impairs STING oligomerization and Golgi localization, reducing STING-dependent inflammation in Trex1-/- mice and STINGN153S/WT bone marrow chimeric mice in a cell-type-specific manner (myeloid cells but not endothelial cells or fibroblasts).","method":"RNF115 knockout cells and mice, disulfiram pharmacological inhibition, STING oligomerization assay, Golgi localization assay (immunofluorescence), bone marrow chimeric mice, cytokine measurement in patient PBMCs","journal":"Cellular & molecular immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO plus pharmacological inhibition plus in vivo mouse models, multiple orthogonal methods, replicated in patient cells","pmids":["38267694"],"is_preprint":false},{"year":2024,"finding":"BCA2 (RNF115) enhances the interaction between MyD88 and TLR4 while inhibiting the interaction of MyD88 with deubiquitinase OTUD4 in LPS-mediated NF-κB signaling, promoting SOX9 expression and breast cancer stemness.","method":"Co-immunoprecipitation, NF-κB signaling assay, BCA2 overexpression/knockdown, SOX9 reporter assay","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP showing altered protein-protein interactions, single lab, functional stemness readout","pmids":["38725852"],"is_preprint":false},{"year":2025,"finding":"RNF115 is an E3 ubiquitin ligase for DHODH, promoting K27-linked ubiquitination of DHODH and inhibiting its autophagic degradation to counteract ferroptosis in hepatocellular carcinoma; YBX1 promotes RNF115 mRNA translation via m5C modification of the 3'-UTR.","method":"Co-IP, ubiquitination assay (K27-specific), autophagy inhibitor experiments, RNF115 knockdown/overexpression, ferroptosis assays (lipid ROS, ferrous ion, 4-HNE), xenograft and DEN-induced HCC models","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — ubiquitination assay with chain-type specificity plus autophagic degradation rescue plus in vivo models, single lab","pmids":["40088428"],"is_preprint":false},{"year":2026,"finding":"RNF115 selectively ubiquitinates the PEDV N protein via K63-linked polyubiquitin chains at K271, K276, K302, K359, and K375; requires RNF115 catalytic residues C25 and C38; the adaptor protein Tollip bridges RNF115 to the N protein in a stable complex, facilitating substrate recognition and autophagic degradation.","method":"Co-immunoprecipitation, site-directed mutagenesis (ubiquitination site mapping and RING domain mutations), K63-linkage-specific ubiquitination assay, RNAi knockdown of Tollip, viral replication assay","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — multiple mutagenesis and chain-type-specific ubiquitination assays with adaptor identification, but single lab and very recent/unreviewed","pmids":["41587704"],"is_preprint":false}],"current_model":"RNF115 (BCA2/Rabring7) is a RING-H2 type E3 ubiquitin (and SUMO) ligase whose activity requires Cys-229 of the RING domain and whose N-terminal BZF zinc finger binds ubiquitin/ubiquitinated proteins; it is recruited by GTP-bound Rab7 to late endosomes/lysosomes where it regulates endosomal sorting and degradation of membrane receptors (EGFR, MET, CXCR4) and, in tetherin-positive cells, promotes lysosomal degradation of tethered HIV-1 virions; in innate immunity it plays dual roles by constitutively inducing K48-linked degradation of MAVS to dampen basal antiviral tone, while catalyzing K63-linked ubiquitination of STING/MITA to promote antiviral and inflammatory signaling, and inhibiting post-ER TLR trafficking via K11-linked ubiquitination of RAB1A and RAB13; its autoubiquitination and stability are regulated by binding partners hHR23a and 14-3-3sigma; it also targets substrates including p21, p53, APC, CDK10, c-Myc, DHODH, and LC3B for ubiquitin-mediated degradation in various cancer and autophagy contexts; and it functions as an E3 SUMO ligase for IκBα to negatively regulate NF-κB signaling."},"narrative":{"mechanistic_narrative":"RNF115 (BCA2/Rabring7) is a RING-H2 type E3 ubiquitin ligase that governs membrane-receptor trafficking, innate immune signaling, and cell proliferation by directing the fate of substrate proteins through linkage-specific ubiquitination [PMID:12972561, PMID:16473630, PMID:23418353, PMID:33139700]. Its catalytic activity depends on Cys-229 of the RING domain and prefers Ubc4/Ubc5 as E2 partners, while an N-terminal BZF zinc finger binds ubiquitin and ubiquitinated proteins and is required for substrate engagement and autoubiquitination [PMID:17462600, PMID:18819927]. Recruited from the cytosol to late endosomes/lysosomes by GTP-bound Rab7, RNF115 promotes endosomal sorting and lysosomal degradation of EGFR and other membrane receptors downstream of c-Cbl, with its depletion trapping cargo in late endocytic compartments [PMID:12972561, PMID:16473630, PMID:23418353]. In innate immunity it acts as a bifunctional rheostat: it constitutively drives K48-linked degradation of MAVS to restrain basal antiviral tone, yet catalyzes K63-linked ubiquitination of STING/MITA to promote its Golgi localization, oligomerization, and downstream inflammation [PMID:33139700, PMID:38267694]. AKT1-phosphorylated RNF115 is chaperoned by 14-3-3 to the ER/Golgi, where it places K11-linked chains on RAB1A and RAB13 to block GDI1 recruitment and impair post-ER/post-Golgi TLR trafficking [PMID:35343654]. Across cancers it acts as a pro-proliferative ligase by degrading growth suppressors including p21, p53, APC, and CDK10 [PMID:24027428, PMID:32553631, PMID:33509267, PMID:38376606]. RNF115 stability is itself controlled by binding partners hHR23a and 14-3-3sigma, which inhibit its autoubiquitination [PMID:22315970].","teleology":[{"year":2003,"claim":"Established RNF115 as a Rab7 effector, defining where in the cell it acts before any enzymatic activity was known.","evidence":"GST pull-down, Co-IP, yeast two-hybrid and live-cell imaging showing GTP-Rab7-dependent recruitment to late endosomes/lysosomes","pmids":["12972561","16473630"],"confidence":"High","gaps":["Did not define a catalytic activity","Did not identify direct substrates beyond an EGF-degradation phenotype"]},{"year":2007,"claim":"Demonstrated that RNF115 is a catalytically active E3 ubiquitin ligase, identifying the essential RING residue and E2 partners.","evidence":"In vitro ubiquitination with recombinant E1/E2, RING point mutagenesis (C229S), EGFR degradation assay","pmids":["17462600"],"confidence":"High","gaps":["Chain linkage types not determined","Physiological substrate repertoire unknown"]},{"year":2008,"claim":"Mapped the BZF zinc finger as a ubiquitin-binding module and defined residues controlling autoubiquitination, explaining how the ligase recognizes ubiquitinated cargo.","evidence":"Two-hybrid screening, deletion/point mutagenesis, in vivo ubiquitination, cell migration assay","pmids":["18819927"],"confidence":"High","gaps":["Direct cellular substrates engaged via BZF not yet identified","Mechanism linking activity to migration unresolved"]},{"year":2009,"claim":"Connected RNF115 to antiviral restriction by showing it cooperates with tetherin to route HIV-1 virions to lysosomal degradation.","evidence":"Co-IP with tetherin, RNAi knockdown, virion release and CD63+ vesicle colocalization assays","pmids":["20019814"],"confidence":"High","gaps":["Whether ubiquitination of a specific substrate drives restriction not defined","Tetherin ubiquitination status not established"]},{"year":2012,"claim":"Identified hHR23a and 14-3-3sigma as regulators of RNF115 stability, revealing how its autoubiquitination and abundance are controlled.","evidence":"Yeast/bacterial two-hybrid, in vitro binding, in vivo autoubiquitination assay","pmids":["22315970"],"confidence":"Medium","gaps":["Kinase generating the phospho-form recognized by 14-3-3sigma not identified here","Physiological contexts of stabilization unclear"]},{"year":2013,"claim":"Resolved RNF115's role in receptor downregulation, placing it downstream of c-Cbl in EGFR/MET/CXCR4 sorting and MVB formation.","evidence":"Co-IP, RNAi, EGFR degradation assay, electron microscopy MVB counting, receptor sorting assays","pmids":["23418353"],"confidence":"High","gaps":["Direct ubiquitination targets within the ESCRT pathway not defined","Relationship between BZF ubiquitin binding and ESCRT-II stability mechanistically open"]},{"year":2013,"claim":"Identified p21 as a degradation substrate, establishing a pro-proliferative function in ERα-positive breast cancer.","evidence":"siRNA knockdown, Co-IP, ubiquitination assay, proliferation and p21-knockdown rescue","pmids":["24027428"],"confidence":"High","gaps":["Ubiquitin chain type on p21 not specified","In vivo tumor relevance not tested in this study"]},{"year":2017,"claim":"Extended RNF115 activity beyond ubiquitin by showing it acts as a SUMO ligase for IκBα to dampen NF-κB-driven HIV-1 transcription.","evidence":"SUMO ligase and IκBα SUMOylation assays, NF-κB reporter, HIV-1 transcription assay in CD4+ T cells","pmids":["28122985"],"confidence":"Medium","gaps":["Structural basis for dual ubiquitin/SUMO ligase activity unknown","Generality of IκBα SUMOylation beyond HIV context untested"]},{"year":2020,"claim":"Defined a bifunctional role in innate immunity: K48-linked degradation of MAVS versus K63-linked activation of STING/MITA, with KO mice confirming both arms in vivo.","evidence":"Co-IP, K48/K63 chain-specific ubiquitination assays, Rnf115-/- mice, EMCV/HSV-1 infection","pmids":["33139700"],"confidence":"High","gaps":["How substrate choice and chain-type are switched is unresolved","Upstream signals selecting MAVS vs STING targeting unclear"]},{"year":2020,"claim":"Linked RNF115 to autophagosome maturation through stabilization of STX17, broadening its role to membrane fusion control.","evidence":"Co-IP, RNF115 KO/depletion, autophagy flux assay, electron microscopy, tumor models","pmids":["32980859"],"confidence":"Medium","gaps":["Whether stabilization is via ubiquitination is not defined","Direct versus indirect effect on STX17 unresolved"]},{"year":2020,"claim":"Identified p53 as a degradation substrate driving lung adenocarcinoma proliferation.","evidence":"Ubiquitination assay, RNF115 knockdown, cell cycle flow cytometry, xenograft","pmids":["32553631"],"confidence":"Medium","gaps":["Limited mechanistic detail on direct interaction","Chain linkage and degron not mapped"]},{"year":2021,"claim":"Showed RNF115 activates Wnt/β-catenin signaling by degrading APC, expanding its oncogenic substrate set.","evidence":"Knockdown/overexpression, ubiquitination assay, Wnt/β-catenin reporter","pmids":["33509267"],"confidence":"Medium","gaps":["Direct binding interface not characterized","In vivo relevance limited in abstract-level detail"]},{"year":2022,"claim":"Defined the mechanism by which AKT1-phosphorylated RNF115 controls TLR trafficking via K11-linked ubiquitination of RAB1A/RAB13 and disruption of GDI1 recruitment.","evidence":"Co-IP, chain-specific in vitro ubiquitination, RAB lysine mutagenesis, KO rescue, GDI1 recruitment and TLR trafficking assays","pmids":["35343654"],"confidence":"High","gaps":["Whether the same mechanism operates outside TLR pathways untested","Reversal/deubiquitination of RAB K11 chains not addressed"]},{"year":2022,"claim":"Established a phagosomal role where RNF115 restrains phagosome maturation and antibacterial cytokine responses, protecting tissue during infection.","evidence":"Phagosome proteomics, RNF115 KO cells and mice, maturation and cytokine assays, S. aureus infection","pmids":["36281581"],"confidence":"High","gaps":["Phagosomal substrates of RNF115 not identified","Link to its receptor-sorting function unresolved"]},{"year":2023,"claim":"Connected RNF115 to autophagy regulation and macrophage inflammation by showing it downregulates LC3B and modulates NF-κB/JNK in acute liver injury.","evidence":"Co-IP (RNF115-LC3B), Rnf115 KO mice, autophagy flux, cytokines, macrophage depletion","pmids":["38129372"],"confidence":"Medium","gaps":["Whether LC3B is directly ubiquitinated not shown","Mechanistic link between LC3B downregulation and M1 activation incomplete"]},{"year":2024,"claim":"Added CDK10 as a degradation substrate, linking RNF115 to Raf-1 pathway activation and thyroid carcinoma progression.","evidence":"Co-IP, ubiquitination assay, CDK10 overexpression rescue, in vitro/in vivo tumor models","pmids":["38376606"],"confidence":"Medium","gaps":["Chain type and degron on CDK10 not mapped","Direct versus indirect Raf-1 activation unclear"]},{"year":2024,"claim":"Confirmed RNF115-driven K63 ubiquitination of STING as a druggable node, with disulfiram inhibition reducing STING-dependent autoinflammation in a cell-type-specific manner.","evidence":"RNF115 KO cells/mice, disulfiram inhibition, STING oligomerization and Golgi localization assays, bone marrow chimeras, patient PBMC cytokines","pmids":["38267694"],"confidence":"High","gaps":["Disulfiram selectivity for RNF115 over other targets not fully resolved","Basis for myeloid-restricted dependence unclear"]},{"year":2024,"claim":"Showed BCA2/RNF115 promotes breast cancer stemness by modulating MyD88-TLR4 and MyD88-OTUD4 interactions in NF-κB signaling.","evidence":"Co-IP, NF-κB and SOX9 reporter assays, overexpression/knockdown","pmids":["38725852"],"confidence":"Medium","gaps":["Whether MyD88 or OTUD4 is directly ubiquitinated not established","Catalytic dependence of the stemness effect untested"]},{"year":2025,"claim":"Identified DHODH as a substrate protected from autophagic degradation via K27-linked ubiquitination, linking RNF115 to ferroptosis resistance in HCC, with translation controlled by YBX1/m5C.","evidence":"Co-IP, K27-specific ubiquitination assay, autophagy inhibition, ferroptosis assays, xenograft and DEN-induced HCC models","pmids":["40088428"],"confidence":"Medium","gaps":["Structural basis for K27 chain assembly not defined","How K27 chains block autophagic recognition mechanistically open"]},{"year":2026,"claim":"Showed RNF115 uses the adaptor Tollip to recognize and K63-ubiquitinate the PEDV N protein for autophagic degradation, defining an adaptor-mediated antiviral substrate route.","evidence":"Co-IP, ubiquitination site and RING mutagenesis, K63-specific assay, Tollip RNAi, viral replication assay","pmids":["41587704"],"confidence":"Medium","gaps":["Single recent study not independently confirmed","Discrepant RING residues (C25/C38 here vs C229 in human studies) reflect a different protein/ortholog context not reconciled"]},{"year":null,"claim":"How RNF115 selects among substrates and switches ubiquitin chain linkage (K11, K27, K48, K63) and even between ubiquitin and SUMO conjugation in different compartments remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of substrate/chain-type specificity","Signals that toggle degradative versus activating outputs not defined","Interplay between its trafficking, autophagy, and immune functions not integrated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[1,2,6,9,13]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,7,9,13,16]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[1,8]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[0,3]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,6]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[13]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[13,17]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[9,13,14,17]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[10,15,19]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,6]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,7,11]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8,12,18]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[7,11,16]}],"complexes":[],"partners":["RAB7","EGFR","MAVS","STING1","RAB1A","RAB13","TOLLIP","LC3B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y4L5","full_name":"E3 ubiquitin-protein ligase RNF115","aliases":["RING finger protein 115","RING-type E3 ubiquitin transferase RNF115","Rab7-interacting RING finger protein","Rabring 7","Zinc finger protein 364"],"length_aa":304,"mass_kda":33.7,"function":"E3 ubiquitin-protein ligase that catalyzes the 'Lys-48'- and/or 'Lys-63'-linked polyubiquitination of various substrates and thereby plays a role in a number of signaling pathways including autophagy, innate immunity, cell proliferation and cell death (PubMed:20019814, PubMed:30689267). Plays a role in the endosomal trafficking and degradation of membrane receptors including EGFR, FLT3, MET and CXCR4 through their polyubiquitination. Participates together with BST2 in antiviral immunity by facilitating the internalization of HIV-1 virions into intracellular vesicles leading to their lysosomal degradation (PubMed:20019814). Also possesses an antiviral activity independently of BST2 by promoting retroviral GAG proteins ubiquitination, redistribution to endo-lysosomal compartments and, ultimately, lysosomal degradation (PubMed:24852021). Catalyzes distinct types of ubiquitination on MAVS and STING1 at different phases of viral infection to promote innate antiviral response (PubMed:33139700). Mediates the 'Lys-48'-linked ubiquitination of MAVS leading to its proteasomal degradation and ubiquitinates STING1 via 'Lys-63'-linked polyubiquitination, critical for its oligomerization and the subsequent recruitment of TBK1 (PubMed:33139700). Plays a positive role in the autophagosome-lysosome fusion by interacting with STX17 and enhancing its stability without affecting 'Lys-48'- or 'Lys-63'-linked polyubiquitination levels, which in turn promotes autophagosome maturation (PubMed:32980859). Negatively regulates TLR-induced expression of proinflammatory cytokines by catalyzing 'Lys-11'-linked ubiquitination of RAB1A and RAB13 to inhibit post-ER trafficking of TLRs to the Golgi by RAB1A and subsequently from the Golgi apparatus to the cell surface by RAB13 (PubMed:35343654)","subcellular_location":"Cytoplasm; Nucleus; Endoplasmic reticulum; Golgi apparatus","url":"https://www.uniprot.org/uniprotkb/Q9Y4L5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RNF115","classification":"Not Classified","n_dependent_lines":30,"n_total_lines":1208,"dependency_fraction":0.024834437086092714},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RNF115","total_profiled":1310},"omim":[{"mim_id":"619535","title":"RING FINGER PROTEIN 115; RNF115","url":"https://www.omim.org/entry/619535"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoli","reliability":"Approved"},{"location":"Mitochondria","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RNF115"},"hgnc":{"alias_symbol":["BCA2","Rabring7","CL469780"],"prev_symbol":["ZNF364"]},"alphafold":{"accession":"Q9Y4L5","domains":[{"cath_id":"-","chopping":"20-50","consensus_level":"high","plddt":85.2019,"start":20,"end":50},{"cath_id":"3.30.40.10","chopping":"207-262","consensus_level":"high","plddt":82.9345,"start":207,"end":262}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y4L5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y4L5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y4L5-F1-predicted_aligned_error_v6.png","plddt_mean":59.84},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RNF115","jax_strain_url":"https://www.jax.org/strain/search?query=RNF115"},"sequence":{"accession":"Q9Y4L5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y4L5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y4L5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y4L5"}},"corpus_meta":[{"pmid":"20222671","id":"PMC_20222671","title":"Exploring 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science","url":"https://pubmed.ncbi.nlm.nih.gov/40079889","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":18613,"output_tokens":5529,"usd":0.069387,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13800,"output_tokens":5797,"usd":0.106963,"stage2_stop_reason":"end_turn"},"total_usd":0.17635,"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\": 2003,\n      \"finding\": \"Rabring7 (RNF115) specifically binds the GTP-bound form of Rab7 at its N-terminal portion, is recruited from cytosol to late endosomes/lysosomes by GTP-Rab7, and its overexpression causes perinuclear lysosomal aggregation and affects EGF degradation.\",\n      \"method\": \"GST pull-down, co-immunoprecipitation, CytoTrap yeast two-hybrid, live-cell imaging with LysoTracker\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal GST pulldown and Co-IP with functional localization and phenotypic readout, replicated in follow-up Methods paper (PMID:16473630)\",\n      \"pmids\": [\"12972561\", \"16473630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Rabring7 (RNF115) has E3 ubiquitin ligase activity, preferentially using Ubc4/Ubc5 as E2 partners; autoubiquitination and EGFR degradation-promoting activity require Cys-229 in the RING finger domain (C229S mutation abolishes activity).\",\n      \"method\": \"In vitro ubiquitination assay with recombinant E1/E2 proteins, RING domain point mutagenesis, EGFR degradation assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with mutagenesis, single lab, two orthogonal methods\",\n      \"pmids\": [\"17462600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"BCA2 (RNF115) undergoes autoubiquitination via its RING-H2 domain; the BZF zinc finger domain binds ubiquitin and ubiquitinated proteins; lysines K26/K32 in BZF are required for autoubiquitination; K232/K260 mutations near the RING domain increase autoubiquitination; BCA2 affects breast cancer cell migration.\",\n      \"method\": \"BacterioMatch two-hybrid screening, deletion/point mutagenesis, in vivo ubiquitination assay, cell migration assay\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mutagenesis of active site residues with in vivo ubiquitination assay plus functional cell migration readout, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"18819927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"BCA2 (RNF115) is a tetherin-interacting E3 ubiquitin ligase that, in tetherin-positive cells, restricts HIV-1 particle production by facilitating internalization of virions into CD63+ intracellular vesicles and promoting their lysosomal degradation.\",\n      \"method\": \"Co-immunoprecipitation (tetherin interaction), RNAi knockdown, virion release assay, immunofluorescence for CD63+ vesicle colocalization\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, RNAi loss-of-function with defined phenotype, subcellular localization with functional consequence; replicated in subsequent studies\",\n      \"pmids\": [\"20019814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"BCA2 (RNF115) binds hHR23a and 14-3-3sigma; hHR23a stabilizes BCA2 by inhibiting its autoubiquitination activity; phosphorylated BCA2 is stabilized by 14-3-3sigma via protein-protein interaction.\",\n      \"method\": \"Yeast two-hybrid, bacterial two-hybrid, in vitro binding with tagged proteins, in vivo autoubiquitination assay\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP confirmed binding and functional effect on autoubiquitination; single lab, two orthogonal methods\",\n      \"pmids\": [\"22315970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Rabring7 (RNF115) binds MM-1 and c-Myc; monoubiquitinates MM-1 in the cytoplasm without degradation; ubiquitinates c-Myc in a Thr58-dependent manner; co-expression of Rabring7 and MM-1 leads to c-Myc degradation, requiring nuclear co-localization.\",\n      \"method\": \"Co-immunoprecipitation, in vivo ubiquitination assay, co-transfection/overexpression, knockdown of MM-1, immunofluorescence co-localization\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP plus ubiquitination assay plus KD rescue, single lab\",\n      \"pmids\": [\"22844532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Rabring7 (RNF115) associates with EGFR through its ubiquitin-binding zinc finger domain; promotes EGFR ubiquitination and lysosomal degradation; functions downstream of c-Cbl (binding is reduced in c-Cbl-deficient cells or cells expressing Cbl-70Z); depletion retains EGFR in a late endocytic compartment; also regulates MET degradation and CXCR4 sorting; depletion destabilizes ESCRT-II and reduces multivesicular body formation.\",\n      \"method\": \"Co-immunoprecipitation, RNAi depletion, EGFR degradation assay, electron microscopy (MVB counting), receptor sorting assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, RNAi, EM, receptor degradation), genetic epistasis with c-Cbl, multiple receptor substrates tested\",\n      \"pmids\": [\"23418353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"BCA2 (RNF115) promotes ubiquitination and proteasomal degradation of p21Waf1/Cip1; directly interacts with p21; knockdown of BCA2 increases p21 protein stability and decreases ERα-positive breast cancer cell proliferation; partial rescue of growth arrest by p21 knockdown confirms the pathway.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation, ubiquitination assay, cell proliferation assay, rescue experiment\",\n      \"journal\": \"Neoplasia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct Co-IP, ubiquitination assay, genetic rescue (p21 KD), single lab, multiple orthogonal methods\",\n      \"pmids\": [\"24027428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"BCA2 (RNF115) acts as an E3 SUMO ligase for IκBα SUMOylation, enhancing sequestration of NF-κB components in the cytoplasm; this reduces NF-κB-dependent HIV-1 proviral transcription; BCA2 is induced by NF-κB-activating cytokines providing a negative feedback loop.\",\n      \"method\": \"SUMO ligase assay, NF-κB reporter assay, IκBα SUMOylation assay, HIV-1 transcription assay in CD4+ T cells\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — SUMOylation assay plus reporter assay plus functional HIV transcription readout, single lab\",\n      \"pmids\": [\"28122985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RNF115 constitutively interacts with MAVS and induces K48-linked ubiquitination and proteasomal degradation of MAVS in uninfected cells; after HSV-1 infection, RNF115 associates with MITA/STING and catalyzes K63-linked ubiquitination to promote MITA aggregation and antiviral signaling; Rnf115-/- mice show increased MAVS and impaired MITA aggregation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitin chain-type-specific assays (K48/K63), Rnf115 knockout mice, viral infection assays (EMCV, HSV-1), western blotting for protein levels\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, chain-type-specific ubiquitination assays, KO mice with in vivo phenotype, two distinct substrates/viral contexts\",\n      \"pmids\": [\"33139700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RNF115 interacts with STX17 (syntaxin 17) and enhances its stability, which is required for autophagosome-lysosome fusion; RNF115 deletion impairs autophagosome maturation and causes accumulation of autophagosomes.\",\n      \"method\": \"Co-immunoprecipitation, RNF115 gene knockout/depletion, autophagy flux assay, electron microscopy, in vitro/in vivo tumor models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP plus KO phenotype plus autophagy flux assay, single lab\",\n      \"pmids\": [\"32980859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RNF115 mediates ubiquitination and degradation of p53, promoting lung adenocarcinoma cell proliferation; RNF115 disruption induces G1 phase arrest and reduces tumor growth in a xenograft model.\",\n      \"method\": \"Ubiquitination assay, RNF115 knockdown/disruption, flow cytometry cell cycle analysis, xenograft tumor model\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — ubiquitination assay and loss-of-function phenotype, single lab, limited mechanistic detail in abstract\",\n      \"pmids\": [\"32553631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RNF115 mediates ubiquitination and proteasomal degradation of APC (adenomatous polyposis coli), activating the Wnt/β-catenin signaling pathway in lung adenocarcinoma cells.\",\n      \"method\": \"RNF115 knockdown/overexpression, ubiquitination assay, Wnt/β-catenin pathway reporter assay\",\n      \"journal\": \"Cancer & metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — ubiquitination assay with pathway readout, single lab, limited detail in abstract\",\n      \"pmids\": [\"33509267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"AKT1-phosphorylated RNF115 is chaperoned by 14-3-3 proteins to localize on the ER and Golgi apparatus, where it interacts with RAB1A and RAB13, catalyzing K11-linked ubiquitination at Lys49/Lys61 of RAB1A and Lys46/Lys58 of RAB13; this modification impairs GDI1 recruitment to these RAB proteins, blocking GDP-dissociation and impairing post-ER and post-Golgi TLR trafficking.\",\n      \"method\": \"Co-immunoprecipitation, in vitro ubiquitination assay with chain-type-specific analysis, site-directed mutagenesis (RAB1A/RAB13 lysine mutants), Rnf115 KO cells with reconstitution, TLR trafficking assay\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro ubiquitination with mutagenesis of specific lysines, KO rescue experiments, GDI1 recruitment assay as mechanistic readout, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"35343654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RNF115 is enriched on phagosomes of IFN-γ-activated macrophages; loss of RNF115 protein or its ligase activity enhances phagosomal maturation and increases cytokine responses to bacterial infection; RNF115 knockout mice show less tissue damage during S. aureus infection.\",\n      \"method\": \"Quantitative proteomics of phagosomes, RNF115 knockout cells and mice, phagosomal maturation assay, cytokine measurement, S. aureus infection model\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — quantitative proteomics plus KO with defined phenotype plus in vivo mouse model, multiple orthogonal methods\",\n      \"pmids\": [\"36281581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RNF115 interacts with LC3B and downregulates LC3B protein levels and cellular autophagy; RNF115 deletion promotes autophagy and inhibits M1 macrophage activation via NF-κB and JNK pathways, protecting against acute liver injury.\",\n      \"method\": \"Co-immunoprecipitation (RNF115-LC3B), Rnf115 KO mice, autophagy flux assay, cytokine measurement, macrophage depletion experiment\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP plus KO mice with defined phenotype and macrophage depletion rescue, single lab\",\n      \"pmids\": [\"38129372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RNF115 ubiquitinates and promotes degradation of CDK10 in thyroid carcinoma cells, thereby activating the Raf-1 pathway and enhancing cell cycle progression; CDK10 overexpression counteracts RNF115-mediated malignant phenotypes.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, CDK10 overexpression rescue, in vitro and in vivo tumor models, Raf-1 pathway analysis\",\n      \"journal\": \"Cell biology and toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — ubiquitination assay plus genetic rescue plus in vivo model, single lab\",\n      \"pmids\": [\"38376606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RNF115 promotes K63-linked ubiquitination of STING/MITA and its Golgi localization/oligomerization; knockout or pharmacological inhibition of RNF115 by disulfiram impairs STING oligomerization and Golgi localization, reducing STING-dependent inflammation in Trex1-/- mice and STINGN153S/WT bone marrow chimeric mice in a cell-type-specific manner (myeloid cells but not endothelial cells or fibroblasts).\",\n      \"method\": \"RNF115 knockout cells and mice, disulfiram pharmacological inhibition, STING oligomerization assay, Golgi localization assay (immunofluorescence), bone marrow chimeric mice, cytokine measurement in patient PBMCs\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO plus pharmacological inhibition plus in vivo mouse models, multiple orthogonal methods, replicated in patient cells\",\n      \"pmids\": [\"38267694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"BCA2 (RNF115) enhances the interaction between MyD88 and TLR4 while inhibiting the interaction of MyD88 with deubiquitinase OTUD4 in LPS-mediated NF-κB signaling, promoting SOX9 expression and breast cancer stemness.\",\n      \"method\": \"Co-immunoprecipitation, NF-κB signaling assay, BCA2 overexpression/knockdown, SOX9 reporter assay\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP showing altered protein-protein interactions, single lab, functional stemness readout\",\n      \"pmids\": [\"38725852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RNF115 is an E3 ubiquitin ligase for DHODH, promoting K27-linked ubiquitination of DHODH and inhibiting its autophagic degradation to counteract ferroptosis in hepatocellular carcinoma; YBX1 promotes RNF115 mRNA translation via m5C modification of the 3'-UTR.\",\n      \"method\": \"Co-IP, ubiquitination assay (K27-specific), autophagy inhibitor experiments, RNF115 knockdown/overexpression, ferroptosis assays (lipid ROS, ferrous ion, 4-HNE), xenograft and DEN-induced HCC models\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — ubiquitination assay with chain-type specificity plus autophagic degradation rescue plus in vivo models, single lab\",\n      \"pmids\": [\"40088428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"RNF115 selectively ubiquitinates the PEDV N protein via K63-linked polyubiquitin chains at K271, K276, K302, K359, and K375; requires RNF115 catalytic residues C25 and C38; the adaptor protein Tollip bridges RNF115 to the N protein in a stable complex, facilitating substrate recognition and autophagic degradation.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis (ubiquitination site mapping and RING domain mutations), K63-linkage-specific ubiquitination assay, RNAi knockdown of Tollip, viral replication assay\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — multiple mutagenesis and chain-type-specific ubiquitination assays with adaptor identification, but single lab and very recent/unreviewed\",\n      \"pmids\": [\"41587704\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RNF115 (BCA2/Rabring7) is a RING-H2 type E3 ubiquitin (and SUMO) ligase whose activity requires Cys-229 of the RING domain and whose N-terminal BZF zinc finger binds ubiquitin/ubiquitinated proteins; it is recruited by GTP-bound Rab7 to late endosomes/lysosomes where it regulates endosomal sorting and degradation of membrane receptors (EGFR, MET, CXCR4) and, in tetherin-positive cells, promotes lysosomal degradation of tethered HIV-1 virions; in innate immunity it plays dual roles by constitutively inducing K48-linked degradation of MAVS to dampen basal antiviral tone, while catalyzing K63-linked ubiquitination of STING/MITA to promote antiviral and inflammatory signaling, and inhibiting post-ER TLR trafficking via K11-linked ubiquitination of RAB1A and RAB13; its autoubiquitination and stability are regulated by binding partners hHR23a and 14-3-3sigma; it also targets substrates including p21, p53, APC, CDK10, c-Myc, DHODH, and LC3B for ubiquitin-mediated degradation in various cancer and autophagy contexts; and it functions as an E3 SUMO ligase for IκBα to negatively regulate NF-κB signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RNF115 (BCA2/Rabring7) is a RING-H2 type E3 ubiquitin ligase that governs membrane-receptor trafficking, innate immune signaling, and cell proliferation by directing the fate of substrate proteins through linkage-specific ubiquitination [#0, #6, #9]. Its catalytic activity depends on Cys-229 of the RING domain and prefers Ubc4/Ubc5 as E2 partners, while an N-terminal BZF zinc finger binds ubiquitin and ubiquitinated proteins and is required for substrate engagement and autoubiquitination [#1, #2]. Recruited from the cytosol to late endosomes/lysosomes by GTP-bound Rab7, RNF115 promotes endosomal sorting and lysosomal degradation of EGFR and other membrane receptors downstream of c-Cbl, with its depletion trapping cargo in late endocytic compartments [#0, #6]. In innate immunity it acts as a bifunctional rheostat: it constitutively drives K48-linked degradation of MAVS to restrain basal antiviral tone, yet catalyzes K63-linked ubiquitination of STING/MITA to promote its Golgi localization, oligomerization, and downstream inflammation [#9, #17]. AKT1-phosphorylated RNF115 is chaperoned by 14-3-3 to the ER/Golgi, where it places K11-linked chains on RAB1A and RAB13 to block GDI1 recruitment and impair post-ER/post-Golgi TLR trafficking [#13]. Across cancers it acts as a pro-proliferative ligase by degrading growth suppressors including p21, p53, APC, and CDK10 [#7, #11, #12, #16]. RNF115 stability is itself controlled by binding partners hHR23a and 14-3-3sigma, which inhibit its autoubiquitination [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established RNF115 as a Rab7 effector, defining where in the cell it acts before any enzymatic activity was known.\",\n      \"evidence\": \"GST pull-down, Co-IP, yeast two-hybrid and live-cell imaging showing GTP-Rab7-dependent recruitment to late endosomes/lysosomes\",\n      \"pmids\": [\"12972561\", \"16473630\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define a catalytic activity\", \"Did not identify direct substrates beyond an EGF-degradation phenotype\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrated that RNF115 is a catalytically active E3 ubiquitin ligase, identifying the essential RING residue and E2 partners.\",\n      \"evidence\": \"In vitro ubiquitination with recombinant E1/E2, RING point mutagenesis (C229S), EGFR degradation assay\",\n      \"pmids\": [\"17462600\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Chain linkage types not determined\", \"Physiological substrate repertoire unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Mapped the BZF zinc finger as a ubiquitin-binding module and defined residues controlling autoubiquitination, explaining how the ligase recognizes ubiquitinated cargo.\",\n      \"evidence\": \"Two-hybrid screening, deletion/point mutagenesis, in vivo ubiquitination, cell migration assay\",\n      \"pmids\": [\"18819927\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct cellular substrates engaged via BZF not yet identified\", \"Mechanism linking activity to migration unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Connected RNF115 to antiviral restriction by showing it cooperates with tetherin to route HIV-1 virions to lysosomal degradation.\",\n      \"evidence\": \"Co-IP with tetherin, RNAi knockdown, virion release and CD63+ vesicle colocalization assays\",\n      \"pmids\": [\"20019814\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ubiquitination of a specific substrate drives restriction not defined\", \"Tetherin ubiquitination status not established\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified hHR23a and 14-3-3sigma as regulators of RNF115 stability, revealing how its autoubiquitination and abundance are controlled.\",\n      \"evidence\": \"Yeast/bacterial two-hybrid, in vitro binding, in vivo autoubiquitination assay\",\n      \"pmids\": [\"22315970\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinase generating the phospho-form recognized by 14-3-3sigma not identified here\", \"Physiological contexts of stabilization unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved RNF115's role in receptor downregulation, placing it downstream of c-Cbl in EGFR/MET/CXCR4 sorting and MVB formation.\",\n      \"evidence\": \"Co-IP, RNAi, EGFR degradation assay, electron microscopy MVB counting, receptor sorting assays\",\n      \"pmids\": [\"23418353\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct ubiquitination targets within the ESCRT pathway not defined\", \"Relationship between BZF ubiquitin binding and ESCRT-II stability mechanistically open\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified p21 as a degradation substrate, establishing a pro-proliferative function in ER\\u03b1-positive breast cancer.\",\n      \"evidence\": \"siRNA knockdown, Co-IP, ubiquitination assay, proliferation and p21-knockdown rescue\",\n      \"pmids\": [\"24027428\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitin chain type on p21 not specified\", \"In vivo tumor relevance not tested in this study\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended RNF115 activity beyond ubiquitin by showing it acts as a SUMO ligase for I\\u03baB\\u03b1 to dampen NF-\\u03baB-driven HIV-1 transcription.\",\n      \"evidence\": \"SUMO ligase and I\\u03baB\\u03b1 SUMOylation assays, NF-\\u03baB reporter, HIV-1 transcription assay in CD4+ T cells\",\n      \"pmids\": [\"28122985\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis for dual ubiquitin/SUMO ligase activity unknown\", \"Generality of I\\u03baB\\u03b1 SUMOylation beyond HIV context untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined a bifunctional role in innate immunity: K48-linked degradation of MAVS versus K63-linked activation of STING/MITA, with KO mice confirming both arms in vivo.\",\n      \"evidence\": \"Co-IP, K48/K63 chain-specific ubiquitination assays, Rnf115-/- mice, EMCV/HSV-1 infection\",\n      \"pmids\": [\"33139700\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How substrate choice and chain-type are switched is unresolved\", \"Upstream signals selecting MAVS vs STING targeting unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linked RNF115 to autophagosome maturation through stabilization of STX17, broadening its role to membrane fusion control.\",\n      \"evidence\": \"Co-IP, RNF115 KO/depletion, autophagy flux assay, electron microscopy, tumor models\",\n      \"pmids\": [\"32980859\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether stabilization is via ubiquitination is not defined\", \"Direct versus indirect effect on STX17 unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified p53 as a degradation substrate driving lung adenocarcinoma proliferation.\",\n      \"evidence\": \"Ubiquitination assay, RNF115 knockdown, cell cycle flow cytometry, xenograft\",\n      \"pmids\": [\"32553631\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Limited mechanistic detail on direct interaction\", \"Chain linkage and degron not mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed RNF115 activates Wnt/\\u03b2-catenin signaling by degrading APC, expanding its oncogenic substrate set.\",\n      \"evidence\": \"Knockdown/overexpression, ubiquitination assay, Wnt/\\u03b2-catenin reporter\",\n      \"pmids\": [\"33509267\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding interface not characterized\", \"In vivo relevance limited in abstract-level detail\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined the mechanism by which AKT1-phosphorylated RNF115 controls TLR trafficking via K11-linked ubiquitination of RAB1A/RAB13 and disruption of GDI1 recruitment.\",\n      \"evidence\": \"Co-IP, chain-specific in vitro ubiquitination, RAB lysine mutagenesis, KO rescue, GDI1 recruitment and TLR trafficking assays\",\n      \"pmids\": [\"35343654\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the same mechanism operates outside TLR pathways untested\", \"Reversal/deubiquitination of RAB K11 chains not addressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established a phagosomal role where RNF115 restrains phagosome maturation and antibacterial cytokine responses, protecting tissue during infection.\",\n      \"evidence\": \"Phagosome proteomics, RNF115 KO cells and mice, maturation and cytokine assays, S. aureus infection\",\n      \"pmids\": [\"36281581\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phagosomal substrates of RNF115 not identified\", \"Link to its receptor-sorting function unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected RNF115 to autophagy regulation and macrophage inflammation by showing it downregulates LC3B and modulates NF-\\u03baB/JNK in acute liver injury.\",\n      \"evidence\": \"Co-IP (RNF115-LC3B), Rnf115 KO mice, autophagy flux, cytokines, macrophage depletion\",\n      \"pmids\": [\"38129372\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether LC3B is directly ubiquitinated not shown\", \"Mechanistic link between LC3B downregulation and M1 activation incomplete\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Added CDK10 as a degradation substrate, linking RNF115 to Raf-1 pathway activation and thyroid carcinoma progression.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, CDK10 overexpression rescue, in vitro/in vivo tumor models\",\n      \"pmids\": [\"38376606\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Chain type and degron on CDK10 not mapped\", \"Direct versus indirect Raf-1 activation unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Confirmed RNF115-driven K63 ubiquitination of STING as a druggable node, with disulfiram inhibition reducing STING-dependent autoinflammation in a cell-type-specific manner.\",\n      \"evidence\": \"RNF115 KO cells/mice, disulfiram inhibition, STING oligomerization and Golgi localization assays, bone marrow chimeras, patient PBMC cytokines\",\n      \"pmids\": [\"38267694\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Disulfiram selectivity for RNF115 over other targets not fully resolved\", \"Basis for myeloid-restricted dependence unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed BCA2/RNF115 promotes breast cancer stemness by modulating MyD88-TLR4 and MyD88-OTUD4 interactions in NF-\\u03baB signaling.\",\n      \"evidence\": \"Co-IP, NF-\\u03baB and SOX9 reporter assays, overexpression/knockdown\",\n      \"pmids\": [\"38725852\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MyD88 or OTUD4 is directly ubiquitinated not established\", \"Catalytic dependence of the stemness effect untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified DHODH as a substrate protected from autophagic degradation via K27-linked ubiquitination, linking RNF115 to ferroptosis resistance in HCC, with translation controlled by YBX1/m5C.\",\n      \"evidence\": \"Co-IP, K27-specific ubiquitination assay, autophagy inhibition, ferroptosis assays, xenograft and DEN-induced HCC models\",\n      \"pmids\": [\"40088428\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis for K27 chain assembly not defined\", \"How K27 chains block autophagic recognition mechanistically open\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showed RNF115 uses the adaptor Tollip to recognize and K63-ubiquitinate the PEDV N protein for autophagic degradation, defining an adaptor-mediated antiviral substrate route.\",\n      \"evidence\": \"Co-IP, ubiquitination site and RING mutagenesis, K63-specific assay, Tollip RNAi, viral replication assay\",\n      \"pmids\": [\"41587704\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single recent study not independently confirmed\", \"Discrepant RING residues (C25/C38 here vs C229 in human studies) reflect a different protein/ortholog context not reconciled\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RNF115 selects among substrates and switches ubiquitin chain linkage (K11, K27, K48, K63) and even between ubiquitin and SUMO conjugation in different compartments remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of substrate/chain-type specificity\", \"Signals that toggle degradative versus activating outputs not defined\", \"Interplay between its trafficking, autophagy, and immune functions not integrated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [1, 2, 6, 9, 13]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 7, 9, 13, 16]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [1, 8]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [13, 17]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [9, 13, 14, 17]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [10, 15, 19]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 7, 11]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 12, 18]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [7, 11, 16]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RAB7\", \"EGFR\", \"MAVS\", \"STING1\", \"RAB1A\", \"RAB13\", \"TollIP\", \"LC3B\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":7,"faith_pct":100.0}}