{"gene":"RNF26","run_date":"2026-06-10T06:43:37","timeline":{"discoveries":[{"year":2001,"finding":"RNF26 encodes a 433 amino acid protein with an N-terminal leucine zipper domain and a C-terminal RING finger domain (C3HC5 subfamily), consistent with E3 ubiquitin ligase activity.","method":"Molecular cloning, sequence analysis, domain characterization","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — molecular cloning and domain characterization from sequence, structural inference only, no in vitro ubiquitination assay performed","pmids":["11352657"],"is_preprint":false},{"year":2014,"finding":"RNF26 functions as an E3 ubiquitin ligase that promotes K11-linked polyubiquitination of MITA/STING at lysine 150, thereby protecting MITA from RNF5-mediated K48-linked polyubiquitination and proteasomal degradation, which is required for efficient type I IFN induction early after viral infection.","method":"Co-immunoprecipitation, ubiquitination assays, site-directed mutagenesis (K150), knockdown experiments, viral infection assays","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ubiquitination assay with site mutagenesis, functional rescue, multiple cell lines tested","pmids":["25254379"],"is_preprint":false},{"year":2014,"finding":"RNF26 limits excessive type I IFN response at the late phase of viral infection by promoting autophagic degradation of IRF3.","method":"Knockdown experiments, viral infection time-course assays, autophagy pathway analysis","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional knockdown with defined phenotype and temporal resolution, but mechanistic details of IRF3 autophagy targeting are not fully elaborated in the abstract","pmids":["25254379"],"is_preprint":false},{"year":2021,"finding":"The ER-embedded E2/E3 ubiquitylation complex UBE2J1/RNF26 modifies SQSTM1/p62 on lysine 435 to recruit endosomal adaptors, immobilizing endosomes in the perinuclear region and promoting trafficking of activated EGFR to lysosomes, thereby facilitating termination of EGF-induced AKT signaling.","method":"Co-immunoprecipitation, ubiquitylation assays, site-directed mutagenesis (K435), live-cell imaging, subcellular fractionation, signaling assays (AKT phosphorylation)","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, specific substrate site identified by mutagenesis, functional consequence on EGFR/AKT signaling demonstrated with multiple orthogonal methods","pmids":["33472082"],"is_preprint":false},{"year":2021,"finding":"FOXM1 transcriptionally upregulates RNF26 through the MuvB complex, and upregulated RNF26 in turn degrades p57 (CDKN1C) to promote cell cycle progression in bladder cancer.","method":"Chromatin immunoprecipitation (transcriptional regulation), co-immunoprecipitation, Western blot (protein degradation assay), cell cycle analysis","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional axis established with ChIP and protein degradation assays, single lab, but abstract does not describe direct ubiquitination of p57 in vitro","pmids":["34650035"],"is_preprint":false},{"year":2022,"finding":"RNF26 promotes ubiquitination and proteasomal degradation of CBX7, and CBX7 loss de-represses ETS1 to activate the TNF signaling pathway, promoting ccRCC tumor growth.","method":"Co-immunoprecipitation, ubiquitination assay, Western blot (degradation), proliferation assays","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, Co-IP-based identification of substrate, functional downstream pathway defined, no in vitro reconstitution described","pmids":["35342353"],"is_preprint":false},{"year":2023,"finding":"RNF26 binds perinuclear vimentin intermediate filaments via the C-terminus of its RING domain, which restricts RNF26 to perinuclear ER subdomains and enables spatial retention of endolysosomes through RNF26-mediated membrane contact sites (MCS), facilitating efficient recovery from ER stress via the Sec62-mediated ER-phagy pathway.","method":"Co-immunoprecipitation, live-cell imaging, CLEM/electron microscopy, RNF26 and vimentin knockout/knockdown, domain mapping, ER stress assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, imaging, KO, domain mapping, functional ER stress recovery assay), single lab but comprehensive mechanistic dissection","pmids":["37519262"],"is_preprint":false},{"year":2023,"finding":"RNF26 promotes degradation of RBM38 to enhance pancreatic cancer cell proliferation.","method":"Protein-protein interaction network analysis, co-immunoprecipitation, Western blot (degradation assay), cell proliferation assays","journal":"Pancreas","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method (Western blot for degradation), no direct ubiquitination assay described in abstract","pmids":["37099788"],"is_preprint":false},{"year":2024,"finding":"CDK4 phosphorylates RNF26 to enhance its interaction with TSC1; CDK4/6 inhibitors dephosphorylate RNF26, disrupting the RNF26-TSC1 interaction and stabilizing TSC1, thereby inactivating the mTOR signaling pathway. RNF26 functions as an E3 ligase for TSC1.","method":"Mass spectrometry, co-immunoprecipitation, GST pull-down assays, Western blot, phosphorylation analysis, xenograft assays","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mass spectrometry, GST pull-down, and Co-IP together identify substrate and modification, single lab","pmids":["38890443"],"is_preprint":false},{"year":2024,"finding":"PTPRZ1 dephosphorylates RNF26 at Y432, stabilizing RNF26 protein by preventing its proteasomal degradation; stabilized RNF26 activates the TNF/NF-κB signaling pathway to promote ccRCC proliferation and angiogenesis.","method":"Mass spectrometry, co-immunoprecipitation, site-directed analysis (Y432), Western blot (proteasome inhibitor experiments), RNA sequencing, immunohistochemical staining","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mass spectrometry-identified phosphorylation site, proteasome pathway established, Co-IP, single lab with multiple methods","pmids":["39443724"],"is_preprint":false},{"year":2024,"finding":"RNF26 promotes K48-linked polyubiquitination and degradation of TRIM21, and loss of TRIM21 leads to upregulation of ZHX3 as a downstream effector in bladder cancer.","method":"Co-immunoprecipitation, ubiquitination assay, Western blot (degradation), knockdown/overexpression functional assays","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and ubiquitination assay identify substrate, downstream pathway defined, single lab","pmids":["39267687"],"is_preprint":false},{"year":2026,"finding":"RNF26 promotes K48-linked polyubiquitination and degradation of the ER chaperone GRP78, inducing sustained ER stress, which reduces MHC-I antigen presentation and increases PD-L1 expression, thereby suppressing CD8+ T cell infiltration and driving immune evasion in hepatocellular carcinoma.","method":"Molecular interaction assays, ubiquitination assays, hepatocyte-specific Rnf26 knockout mouse model, 3D tumor-T cell co-culture, RNA-seq, pharmacological ER stress inhibition","journal":"Drug resistance updates","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods including in vivo KO model, in vitro co-culture, ubiquitination assay, pharmacological rescue, mechanistically linked to immune phenotype","pmids":["41687462"],"is_preprint":false},{"year":2025,"finding":"RNF26 deletion produces nuclear envelope condensates that phenocopy hallmarks of torsin deficiency, linking RNF26 to nuclear condensate homeostasis.","method":"Genome-wide CRISPR/Cas9 screen, high-content imaging, machine learning-based condensate phenotype classification","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single genetic screen, phenotype described but molecular mechanism of condensate formation not established","pmids":["bio_10.1101_2025.06.07.658469"],"is_preprint":true}],"current_model":"RNF26 is an ER-transmembrane E3 ubiquitin ligase that operates in multiple contexts: it partners with UBE2J1 to ubiquitylate SQSTM1/p62 (K435) and perinuclear vimentin-anchored ER subdomains to control endolysosomal positioning and membrane contact sites; it regulates innate immunity by promoting K11-linked ubiquitination of MITA/STING (K150) to protect it from RNF5-mediated degradation during early antiviral response and by promoting autophagic IRF3 degradation at late stages; it ubiquitinates GRP78 (K48-linked) to induce ER stress and immune evasion in HCC; and it targets multiple substrates for proteasomal degradation (CBX7, p57/CDKN1C, TSC1, TRIM21) to modulate cell cycle, mTOR, and TNF/NF-κB signaling, with its own activity regulated by CDK4-mediated phosphorylation and PTPRZ1-mediated dephosphorylation at Y432."},"narrative":{"mechanistic_narrative":"RNF26 is an endoplasmic reticulum-anchored RING-type E3 ubiquitin ligase that organizes endolysosomal positioning, membrane contact sites, and proteostasis, and that acts more broadly as a substrate-selective ligase shaping innate immune and oncogenic signaling [PMID:11352657, PMID:33472082, PMID:37519262]. At the ER membrane it pairs with the E2 enzyme UBE2J1 to ubiquitylate SQSTM1/p62 on K435, recruiting endosomal adaptors that immobilize endosomes in the perinuclear region and route activated EGFR toward lysosomal degradation, thereby terminating EGF-induced AKT signaling [PMID:33472082]. Its perinuclear confinement is achieved through binding of the C-terminus of its RING domain to vimentin intermediate filaments, restricting RNF26 to perinuclear ER subdomains where it builds membrane contact sites that retain endolysosomes and support Sec62-mediated ER-phagy recovery from ER stress [PMID:37519262]. In antiviral immunity, RNF26 catalyzes K11-linked polyubiquitination of MITA/STING at K150 to shield it from RNF5-driven degradation and promote early type I interferon induction, while later restraining the response by promoting autophagic degradation of IRF3 [PMID:25254379]. Across cancer contexts RNF26 directs proteasomal turnover of multiple substrates—CBX7, p57/CDKN1C, TSC1, and TRIM21—to drive cell cycle progression, mTOR activity, and TNF/NF-κB signaling, and its activity is gated by CDK4-mediated phosphorylation and PTPRZ1-mediated dephosphorylation at Y432 [PMID:34650035, PMID:35342353, PMID:38890443, PMID:39443724, PMID:39267687]. RNF26 also K48-ubiquitylates the ER chaperone GRP78 to sustain ER stress, reducing MHC-I antigen presentation and elevating PD-L1 to drive immune evasion in hepatocellular carcinoma [PMID:41687462].","teleology":[{"year":2001,"claim":"Established the protein architecture of RNF26, predicting E3 ligase function from its domain composition before any catalytic activity had been tested.","evidence":"Molecular cloning and sequence/domain analysis identifying an N-terminal leucine zipper and C-terminal C3HC5 RING finger","pmids":["11352657"],"confidence":"Medium","gaps":["No in vitro ubiquitination assay demonstrating catalytic activity","No substrate or partner identified at this stage"]},{"year":2014,"claim":"Defined the first physiological substrate and a biphasic role in antiviral signaling, showing RNF26 both stabilizes STING early and dampens the response late.","evidence":"Reciprocal Co-IP, K150 site-directed ubiquitination assays, knockdown and viral infection time-course assays","pmids":["25254379"],"confidence":"High","gaps":["Mechanism of IRF3 autophagic targeting not fully elaborated","E2 partner for STING ubiquitination not defined in this context"]},{"year":2021,"claim":"Identified the UBE2J1/RNF26 E2/E3 complex and its p62-K435 substrate as the machinery that anchors endosomes perinuclearly and controls EGFR/AKT signaling termination.","evidence":"Reciprocal Co-IP, K435 mutagenesis, live-cell imaging, fractionation, and AKT phosphorylation assays","pmids":["33472082"],"confidence":"High","gaps":["Full set of endosomal adaptors recruited not enumerated","Structural basis of the E2/E3 pairing unresolved"]},{"year":2021,"claim":"Connected RNF26 to cell cycle control via a FOXM1/MuvB transcriptional axis and p57/CDKN1C degradation in bladder cancer.","evidence":"ChIP for transcriptional regulation, Co-IP, and Western blot degradation and cell cycle assays","pmids":["34650035"],"confidence":"Medium","gaps":["No in vitro ubiquitination of p57 demonstrated","Single lab, single tumor context"]},{"year":2022,"claim":"Extended the substrate repertoire to CBX7, linking RNF26 to ETS1 de-repression and TNF pathway activation in ccRCC.","evidence":"Co-IP, ubiquitination assay, degradation Western blot, and proliferation assays","pmids":["35342353"],"confidence":"Medium","gaps":["No in vitro reconstitution of CBX7 ubiquitination","Ubiquitin linkage type not defined"]},{"year":2023,"claim":"Resolved how RNF26 is spatially confined, showing RING-domain binding to vimentin retains it at perinuclear ER and enables membrane contact sites supporting ER-phagy stress recovery.","evidence":"Co-IP, live-cell imaging, CLEM/EM, KO/knockdown, domain mapping, and ER stress recovery assays","pmids":["37519262"],"confidence":"High","gaps":["How RING-domain vimentin binding is reconciled with catalytic ubiquitin transfer unclear","Regulation of MCS dynamics not detailed"]},{"year":2023,"claim":"Added RBM38 as a degradation target promoting pancreatic cancer proliferation.","evidence":"Interaction network analysis, Co-IP, and degradation Western blot with proliferation assays","pmids":["37099788"],"confidence":"Low","gaps":["No direct ubiquitination assay described","Single method for degradation, not independently confirmed"]},{"year":2024,"claim":"Revealed kinase control of RNF26, with CDK4 phosphorylation enhancing TSC1 binding and CDK4/6 inhibitors stabilizing TSC1 to inactivate mTOR.","evidence":"Mass spectrometry, GST pull-down, Co-IP, phosphorylation analysis, and xenograft assays","pmids":["38890443"],"confidence":"Medium","gaps":["Phosphosite on RNF26 not specified in this axis","Direct in vitro ubiquitination of TSC1 not shown"]},{"year":2024,"claim":"Identified PTPRZ1-mediated Y432 dephosphorylation as a stabilizing input that boosts RNF26-driven TNF/NF-κB signaling in ccRCC.","evidence":"Mass spectrometry, Y432 site analysis, Co-IP, proteasome inhibitor Westerns, RNA-seq, and IHC","pmids":["39443724"],"confidence":"Medium","gaps":["Kinase that phosphorylates Y432 not identified","Single lab, single tumor type"]},{"year":2024,"claim":"Added TRIM21 as a K48-linked degradation substrate with ZHX3 as a downstream effector in bladder cancer.","evidence":"Co-IP, ubiquitination assay, degradation Western blot, and knockdown/overexpression assays","pmids":["39267687"],"confidence":"Medium","gaps":["Direct enzymatic reconstitution not described","Mechanism linking TRIM21 loss to ZHX3 upregulation incomplete"]},{"year":2026,"claim":"Linked RNF26 to tumor immune evasion by K48-ubiquitylating GRP78 to sustain ER stress, lowering MHC-I and raising PD-L1 to suppress CD8+ T cell infiltration.","evidence":"Interaction and ubiquitination assays, hepatocyte-specific Rnf26 KO mouse, 3D tumor-T cell co-culture, RNA-seq, and pharmacological ER stress inhibition","pmids":["41687462"],"confidence":"High","gaps":["Site of GRP78 ubiquitination not mapped","Whether ER-positioning function contributes to the ER stress phenotype unclear"]},{"year":2025,"claim":"Implicated RNF26 in nuclear envelope condensate homeostasis through a phenotype resembling torsin deficiency.","evidence":"Genome-wide CRISPR/Cas9 screen with high-content imaging and ML-based condensate classification (preprint)","pmids":["bio_10.1101_2025.06.07.658469"],"confidence":"Low","gaps":["Molecular mechanism of condensate formation not established","Preprint, single genetic screen, awaits mechanistic validation"]},{"year":null,"claim":"How RNF26's ER-membrane positioning/contact-site function is mechanistically coordinated with its diverse substrate-degradation roles, and how a single ligase achieves substrate selectivity across immunity, cell cycle, and proteostasis, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unifying model linking ER-anchored contact-site activity to cytosolic/nuclear substrate degradation","Determinants of substrate and ubiquitin-linkage selectivity uncharacterized","Structural basis of RING activity in the membrane context unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,3,5,8,10,11]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[6]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[3,6,11]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,3,8,10,11]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,2,11]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[3,6]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[6,11]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,8,9]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[4]}],"complexes":["UBE2J1/RNF26 E2/E3 ubiquitylation complex"],"partners":["UBE2J1","SQSTM1","STING1","RNF5","VIMENTIN","TSC1","CBX7","TRIM21"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BY78","full_name":"E3 ubiquitin-protein ligase RNF26","aliases":["RING finger protein 26"],"length_aa":433,"mass_kda":47.7,"function":"E3 ubiquitin-protein ligase that plays a key role in endosome organization by retaining vesicles in the perinuclear cloud (PubMed:27368102). Acts as a platform for perinuclear positioning of the endosomal system by mediating ubiquitination of SQSTM1 through interaction with the ubiquitin conjugating enzyme UBE2J1 (PubMed:27368102, PubMed:33472082). Ubiquitinated SQSTM1 attracts specific vesicle-associated adapters, forming a molecular bridge that restrains cognate vesicles in the perinuclear region and organizes the endosomal pathway for efficient cargo transport (PubMed:27368102, PubMed:33472082). Also acts as a regulator of type I interferon production in response to viral infection by mediating the formation of 'Lys-11'-linked polyubiquitin chains on TMEM173/STING, leading to stabilize TMEM173/STING (PubMed:25254379, PubMed:32614325). Also required to limit type I interferon response by promoting autophagic degradation of IRF3 (PubMed:25254379)","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q9BY78/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RNF26","classification":"Not Classified","n_dependent_lines":23,"n_total_lines":1208,"dependency_fraction":0.01903973509933775},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RNF26","total_profiled":1310},"omim":[{"mim_id":"620096","title":"RING FINGER PROTEIN 185; RNF185","url":"https://www.omim.org/entry/620096"},{"mim_id":"606130","title":"RING FINGER PROTEIN 26; RNF26","url":"https://www.omim.org/entry/606130"},{"mim_id":"602046","title":"PROTEIN DISULFIDE ISOMERASE, FAMILY A, MEMBER 3; PDIA3","url":"https://www.omim.org/entry/602046"},{"mim_id":"114217","title":"CALNEXIN; CANX","url":"https://www.omim.org/entry/114217"},{"mim_id":"109091","title":"CALRETICULIN; CALR","url":"https://www.omim.org/entry/109091"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RNF26"},"hgnc":{"alias_symbol":["MGC2642"],"prev_symbol":[]},"alphafold":{"accession":"Q9BY78","domains":[{"cath_id":"3.30.40.10","chopping":"378-431","consensus_level":"high","plddt":90.8194,"start":378,"end":431},{"cath_id":"1.10.287","chopping":"2-117_134-239","consensus_level":"medium","plddt":83.8895,"start":2,"end":239}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BY78","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BY78-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BY78-F1-predicted_aligned_error_v6.png","plddt_mean":75.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RNF26","jax_strain_url":"https://www.jax.org/strain/search?query=RNF26"},"sequence":{"accession":"Q9BY78","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BY78.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BY78/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BY78"}},"corpus_meta":[{"pmid":"25254379","id":"PMC_25254379","title":"RNF26 temporally regulates virus-triggered type I interferon induction by two distinct mechanisms.","date":"2014","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/25254379","citation_count":177,"is_preprint":false},{"pmid":"11352657","id":"PMC_11352657","title":"Molecular cloning and characterization of RNF26 on human chromosome 11q23 region, encoding a novel RING finger protein with leucine zipper.","date":"2001","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/11352657","citation_count":63,"is_preprint":false},{"pmid":"33472082","id":"PMC_33472082","title":"The ER-embedded UBE2J1/RNF26 ubiquitylation complex exerts spatiotemporal control over the endolysosomal pathway.","date":"2021","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/33472082","citation_count":34,"is_preprint":false},{"pmid":"34650035","id":"PMC_34650035","title":"The FOXM1/RNF26/p57 axis regulates the cell cycle to promote the aggressiveness of bladder cancer.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/34650035","citation_count":33,"is_preprint":false},{"pmid":"35342353","id":"PMC_35342353","title":"The RNF26/CBX7 axis modulates the TNF pathway to promote cell proliferation and regulate sensitivity to TKIs in ccRCC.","date":"2022","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35342353","citation_count":22,"is_preprint":false},{"pmid":"37519262","id":"PMC_37519262","title":"RNF26 binds perinuclear vimentin filaments to integrate ER and endolysosomal responses to proteotoxic stress.","date":"2023","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/37519262","citation_count":20,"is_preprint":false},{"pmid":"39267687","id":"PMC_39267687","title":"RNF26-mediated ubiquitination of TRIM21 promotes bladder cancer progression.","date":"2024","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/39267687","citation_count":6,"is_preprint":false},{"pmid":"37099788","id":"PMC_37099788","title":"RNF26 Promotes Pancreatic Cancer Proliferation by Enhancing RBM38 Degradation.","date":"2023","source":"Pancreas","url":"https://pubmed.ncbi.nlm.nih.gov/37099788","citation_count":3,"is_preprint":false},{"pmid":"38890443","id":"PMC_38890443","title":"CDK4/6 inhibitors dephosphorylate RNF26 to stabilize TSC1 and increase the sensitivity of ccRCC to mTOR inhibitors.","date":"2024","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/38890443","citation_count":2,"is_preprint":false},{"pmid":"39443724","id":"PMC_39443724","title":"PTPRZ1 dephosphorylates and stabilizes RNF26 to reduce the efficacy of TKIs and PD-1 blockade in ccRCC.","date":"2024","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/39443724","citation_count":1,"is_preprint":false},{"pmid":"41687462","id":"PMC_41687462","title":"RNF26 regulating tumor immunogenicity of hepatocellular carcinoma by degrading GRP78 and instigating ER stress.","date":"2026","source":"Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/41687462","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.06.07.658469","title":"Integrative Chemical Genetics Platform Identifies Condensate Modulators Linked to Neurological Disorders","date":"2025-06-08","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.07.658469","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7719,"output_tokens":3074,"usd":0.034633,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10450,"output_tokens":4034,"usd":0.07655,"stage2_stop_reason":"end_turn"},"total_usd":0.111183,"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\": 2001,\n      \"finding\": \"RNF26 encodes a 433 amino acid protein with an N-terminal leucine zipper domain and a C-terminal RING finger domain (C3HC5 subfamily), consistent with E3 ubiquitin ligase activity.\",\n      \"method\": \"Molecular cloning, sequence analysis, domain characterization\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — molecular cloning and domain characterization from sequence, structural inference only, no in vitro ubiquitination assay performed\",\n      \"pmids\": [\"11352657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RNF26 functions as an E3 ubiquitin ligase that promotes K11-linked polyubiquitination of MITA/STING at lysine 150, thereby protecting MITA from RNF5-mediated K48-linked polyubiquitination and proteasomal degradation, which is required for efficient type I IFN induction early after viral infection.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, site-directed mutagenesis (K150), knockdown experiments, viral infection assays\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ubiquitination assay with site mutagenesis, functional rescue, multiple cell lines tested\",\n      \"pmids\": [\"25254379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RNF26 limits excessive type I IFN response at the late phase of viral infection by promoting autophagic degradation of IRF3.\",\n      \"method\": \"Knockdown experiments, viral infection time-course assays, autophagy pathway analysis\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional knockdown with defined phenotype and temporal resolution, but mechanistic details of IRF3 autophagy targeting are not fully elaborated in the abstract\",\n      \"pmids\": [\"25254379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The ER-embedded E2/E3 ubiquitylation complex UBE2J1/RNF26 modifies SQSTM1/p62 on lysine 435 to recruit endosomal adaptors, immobilizing endosomes in the perinuclear region and promoting trafficking of activated EGFR to lysosomes, thereby facilitating termination of EGF-induced AKT signaling.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitylation assays, site-directed mutagenesis (K435), live-cell imaging, subcellular fractionation, signaling assays (AKT phosphorylation)\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, specific substrate site identified by mutagenesis, functional consequence on EGFR/AKT signaling demonstrated with multiple orthogonal methods\",\n      \"pmids\": [\"33472082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FOXM1 transcriptionally upregulates RNF26 through the MuvB complex, and upregulated RNF26 in turn degrades p57 (CDKN1C) to promote cell cycle progression in bladder cancer.\",\n      \"method\": \"Chromatin immunoprecipitation (transcriptional regulation), co-immunoprecipitation, Western blot (protein degradation assay), cell cycle analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional axis established with ChIP and protein degradation assays, single lab, but abstract does not describe direct ubiquitination of p57 in vitro\",\n      \"pmids\": [\"34650035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RNF26 promotes ubiquitination and proteasomal degradation of CBX7, and CBX7 loss de-represses ETS1 to activate the TNF signaling pathway, promoting ccRCC tumor growth.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, Western blot (degradation), proliferation assays\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, Co-IP-based identification of substrate, functional downstream pathway defined, no in vitro reconstitution described\",\n      \"pmids\": [\"35342353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RNF26 binds perinuclear vimentin intermediate filaments via the C-terminus of its RING domain, which restricts RNF26 to perinuclear ER subdomains and enables spatial retention of endolysosomes through RNF26-mediated membrane contact sites (MCS), facilitating efficient recovery from ER stress via the Sec62-mediated ER-phagy pathway.\",\n      \"method\": \"Co-immunoprecipitation, live-cell imaging, CLEM/electron microscopy, RNF26 and vimentin knockout/knockdown, domain mapping, ER stress assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, imaging, KO, domain mapping, functional ER stress recovery assay), single lab but comprehensive mechanistic dissection\",\n      \"pmids\": [\"37519262\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RNF26 promotes degradation of RBM38 to enhance pancreatic cancer cell proliferation.\",\n      \"method\": \"Protein-protein interaction network analysis, co-immunoprecipitation, Western blot (degradation assay), cell proliferation assays\",\n      \"journal\": \"Pancreas\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (Western blot for degradation), no direct ubiquitination assay described in abstract\",\n      \"pmids\": [\"37099788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CDK4 phosphorylates RNF26 to enhance its interaction with TSC1; CDK4/6 inhibitors dephosphorylate RNF26, disrupting the RNF26-TSC1 interaction and stabilizing TSC1, thereby inactivating the mTOR signaling pathway. RNF26 functions as an E3 ligase for TSC1.\",\n      \"method\": \"Mass spectrometry, co-immunoprecipitation, GST pull-down assays, Western blot, phosphorylation analysis, xenograft assays\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mass spectrometry, GST pull-down, and Co-IP together identify substrate and modification, single lab\",\n      \"pmids\": [\"38890443\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PTPRZ1 dephosphorylates RNF26 at Y432, stabilizing RNF26 protein by preventing its proteasomal degradation; stabilized RNF26 activates the TNF/NF-κB signaling pathway to promote ccRCC proliferation and angiogenesis.\",\n      \"method\": \"Mass spectrometry, co-immunoprecipitation, site-directed analysis (Y432), Western blot (proteasome inhibitor experiments), RNA sequencing, immunohistochemical staining\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mass spectrometry-identified phosphorylation site, proteasome pathway established, Co-IP, single lab with multiple methods\",\n      \"pmids\": [\"39443724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RNF26 promotes K48-linked polyubiquitination and degradation of TRIM21, and loss of TRIM21 leads to upregulation of ZHX3 as a downstream effector in bladder cancer.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, Western blot (degradation), knockdown/overexpression functional assays\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and ubiquitination assay identify substrate, downstream pathway defined, single lab\",\n      \"pmids\": [\"39267687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"RNF26 promotes K48-linked polyubiquitination and degradation of the ER chaperone GRP78, inducing sustained ER stress, which reduces MHC-I antigen presentation and increases PD-L1 expression, thereby suppressing CD8+ T cell infiltration and driving immune evasion in hepatocellular carcinoma.\",\n      \"method\": \"Molecular interaction assays, ubiquitination assays, hepatocyte-specific Rnf26 knockout mouse model, 3D tumor-T cell co-culture, RNA-seq, pharmacological ER stress inhibition\",\n      \"journal\": \"Drug resistance updates\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods including in vivo KO model, in vitro co-culture, ubiquitination assay, pharmacological rescue, mechanistically linked to immune phenotype\",\n      \"pmids\": [\"41687462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RNF26 deletion produces nuclear envelope condensates that phenocopy hallmarks of torsin deficiency, linking RNF26 to nuclear condensate homeostasis.\",\n      \"method\": \"Genome-wide CRISPR/Cas9 screen, high-content imaging, machine learning-based condensate phenotype classification\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single genetic screen, phenotype described but molecular mechanism of condensate formation not established\",\n      \"pmids\": [\"bio_10.1101_2025.06.07.658469\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"RNF26 is an ER-transmembrane E3 ubiquitin ligase that operates in multiple contexts: it partners with UBE2J1 to ubiquitylate SQSTM1/p62 (K435) and perinuclear vimentin-anchored ER subdomains to control endolysosomal positioning and membrane contact sites; it regulates innate immunity by promoting K11-linked ubiquitination of MITA/STING (K150) to protect it from RNF5-mediated degradation during early antiviral response and by promoting autophagic IRF3 degradation at late stages; it ubiquitinates GRP78 (K48-linked) to induce ER stress and immune evasion in HCC; and it targets multiple substrates for proteasomal degradation (CBX7, p57/CDKN1C, TSC1, TRIM21) to modulate cell cycle, mTOR, and TNF/NF-κB signaling, with its own activity regulated by CDK4-mediated phosphorylation and PTPRZ1-mediated dephosphorylation at Y432.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RNF26 is an endoplasmic reticulum-anchored RING-type E3 ubiquitin ligase that organizes endolysosomal positioning, membrane contact sites, and proteostasis, and that acts more broadly as a substrate-selective ligase shaping innate immune and oncogenic signaling [#0, #3, #6]. At the ER membrane it pairs with the E2 enzyme UBE2J1 to ubiquitylate SQSTM1/p62 on K435, recruiting endosomal adaptors that immobilize endosomes in the perinuclear region and route activated EGFR toward lysosomal degradation, thereby terminating EGF-induced AKT signaling [#3]. Its perinuclear confinement is achieved through binding of the C-terminus of its RING domain to vimentin intermediate filaments, restricting RNF26 to perinuclear ER subdomains where it builds membrane contact sites that retain endolysosomes and support Sec62-mediated ER-phagy recovery from ER stress [#6]. In antiviral immunity, RNF26 catalyzes K11-linked polyubiquitination of MITA/STING at K150 to shield it from RNF5-driven degradation and promote early type I interferon induction, while later restraining the response by promoting autophagic degradation of IRF3 [#1, #2]. Across cancer contexts RNF26 directs proteasomal turnover of multiple substrates—CBX7, p57/CDKN1C, TSC1, and TRIM21—to drive cell cycle progression, mTOR activity, and TNF/NF-\\u03baB signaling, and its activity is gated by CDK4-mediated phosphorylation and PTPRZ1-mediated dephosphorylation at Y432 [#4, #5, #8, #9, #10]. RNF26 also K48-ubiquitylates the ER chaperone GRP78 to sustain ER stress, reducing MHC-I antigen presentation and elevating PD-L1 to drive immune evasion in hepatocellular carcinoma [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established the protein architecture of RNF26, predicting E3 ligase function from its domain composition before any catalytic activity had been tested.\",\n      \"evidence\": \"Molecular cloning and sequence/domain analysis identifying an N-terminal leucine zipper and C-terminal C3HC5 RING finger\",\n      \"pmids\": [\"11352657\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro ubiquitination assay demonstrating catalytic activity\", \"No substrate or partner identified at this stage\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined the first physiological substrate and a biphasic role in antiviral signaling, showing RNF26 both stabilizes STING early and dampens the response late.\",\n      \"evidence\": \"Reciprocal Co-IP, K150 site-directed ubiquitination assays, knockdown and viral infection time-course assays\",\n      \"pmids\": [\"25254379\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of IRF3 autophagic targeting not fully elaborated\", \"E2 partner for STING ubiquitination not defined in this context\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified the UBE2J1/RNF26 E2/E3 complex and its p62-K435 substrate as the machinery that anchors endosomes perinuclearly and controls EGFR/AKT signaling termination.\",\n      \"evidence\": \"Reciprocal Co-IP, K435 mutagenesis, live-cell imaging, fractionation, and AKT phosphorylation assays\",\n      \"pmids\": [\"33472082\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full set of endosomal adaptors recruited not enumerated\", \"Structural basis of the E2/E3 pairing unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected RNF26 to cell cycle control via a FOXM1/MuvB transcriptional axis and p57/CDKN1C degradation in bladder cancer.\",\n      \"evidence\": \"ChIP for transcriptional regulation, Co-IP, and Western blot degradation and cell cycle assays\",\n      \"pmids\": [\"34650035\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro ubiquitination of p57 demonstrated\", \"Single lab, single tumor context\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended the substrate repertoire to CBX7, linking RNF26 to ETS1 de-repression and TNF pathway activation in ccRCC.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, degradation Western blot, and proliferation assays\",\n      \"pmids\": [\"35342353\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro reconstitution of CBX7 ubiquitination\", \"Ubiquitin linkage type not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Resolved how RNF26 is spatially confined, showing RING-domain binding to vimentin retains it at perinuclear ER and enables membrane contact sites supporting ER-phagy stress recovery.\",\n      \"evidence\": \"Co-IP, live-cell imaging, CLEM/EM, KO/knockdown, domain mapping, and ER stress recovery assays\",\n      \"pmids\": [\"37519262\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How RING-domain vimentin binding is reconciled with catalytic ubiquitin transfer unclear\", \"Regulation of MCS dynamics not detailed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Added RBM38 as a degradation target promoting pancreatic cancer proliferation.\",\n      \"evidence\": \"Interaction network analysis, Co-IP, and degradation Western blot with proliferation assays\",\n      \"pmids\": [\"37099788\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct ubiquitination assay described\", \"Single method for degradation, not independently confirmed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed kinase control of RNF26, with CDK4 phosphorylation enhancing TSC1 binding and CDK4/6 inhibitors stabilizing TSC1 to inactivate mTOR.\",\n      \"evidence\": \"Mass spectrometry, GST pull-down, Co-IP, phosphorylation analysis, and xenograft assays\",\n      \"pmids\": [\"38890443\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phosphosite on RNF26 not specified in this axis\", \"Direct in vitro ubiquitination of TSC1 not shown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified PTPRZ1-mediated Y432 dephosphorylation as a stabilizing input that boosts RNF26-driven TNF/NF-\\u03baB signaling in ccRCC.\",\n      \"evidence\": \"Mass spectrometry, Y432 site analysis, Co-IP, proteasome inhibitor Westerns, RNA-seq, and IHC\",\n      \"pmids\": [\"39443724\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinase that phosphorylates Y432 not identified\", \"Single lab, single tumor type\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Added TRIM21 as a K48-linked degradation substrate with ZHX3 as a downstream effector in bladder cancer.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, degradation Western blot, and knockdown/overexpression assays\",\n      \"pmids\": [\"39267687\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct enzymatic reconstitution not described\", \"Mechanism linking TRIM21 loss to ZHX3 upregulation incomplete\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Linked RNF26 to tumor immune evasion by K48-ubiquitylating GRP78 to sustain ER stress, lowering MHC-I and raising PD-L1 to suppress CD8+ T cell infiltration.\",\n      \"evidence\": \"Interaction and ubiquitination assays, hepatocyte-specific Rnf26 KO mouse, 3D tumor-T cell co-culture, RNA-seq, and pharmacological ER stress inhibition\",\n      \"pmids\": [\"41687462\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Site of GRP78 ubiquitination not mapped\", \"Whether ER-positioning function contributes to the ER stress phenotype unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated RNF26 in nuclear envelope condensate homeostasis through a phenotype resembling torsin deficiency.\",\n      \"evidence\": \"Genome-wide CRISPR/Cas9 screen with high-content imaging and ML-based condensate classification (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.06.07.658469\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Molecular mechanism of condensate formation not established\", \"Preprint, single genetic screen, awaits mechanistic validation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RNF26's ER-membrane positioning/contact-site function is mechanistically coordinated with its diverse substrate-degradation roles, and how a single ligase achieves substrate selectivity across immunity, cell cycle, and proteostasis, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unifying model linking ER-anchored contact-site activity to cytosolic/nuclear substrate degradation\", \"Determinants of substrate and ubiquitin-linkage selectivity uncharacterized\", \"Structural basis of RING activity in the membrane context unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 3, 5, 8, 10, 11]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [3, 6, 11]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 3, 8, 10, 11]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 2, 11]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [3, 6]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [6, 11]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 8, 9]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [\"UBE2J1/RNF26 E2/E3 ubiquitylation complex\"],\n    \"partners\": [\"UBE2J1\", \"SQSTM1\", \"STING1\", \"RNF5\", \"vimentin\", \"TSC1\", \"CBX7\", \"TRIM21\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}