{"gene":"YIPF5","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2009,"finding":"Yip1A (YIPF5) localizes to the ER-Golgi intermediate compartment (ERGIC) and regulates COPI-independent retrograde transport from the Golgi to the ER. Knockdown delayed Shiga toxin transport from Golgi to ER but did not affect anterograde VSVGts045 transport. The N-terminal cytoplasmic domain of Yip1A inhibited COPI-independent retrograde transport of GT-GFP. Yip1A knockdown also caused dissociation of Rab6 from membranes.","method":"RNAi knockdown, recombinant N-terminal domain inhibition assay, intracellular transport assays, immunofluorescence, membrane fractionation","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple transport assays with specific cargo readouts, single lab, orthogonal methods (RNAi + recombinant domain inhibition + Rab6 membrane recruitment)","pmids":["19509059"],"is_preprint":false},{"year":2010,"finding":"Yip1A (YIPF5) is required for ER network dispersal; depletion causes restructuring of the ER into concentric whorls and markedly slows COPII-mediated protein export. A single conserved amino acid substitution (E95K) in the N-terminal cytoplasmic domain blocks the ER network dispersal function of Yip1A.","method":"RNAi depletion, live-cell and electron microscopy of ER morphology, COPII cargo export assays, site-directed mutagenesis (E95K)","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — active-site mutagenesis (E95K) combined with morphological and functional export assays; multiple orthogonal methods in one rigorous study","pmids":["20237155"],"is_preprint":false},{"year":2013,"finding":"Mutational analysis of Yip1A identified two discrete functionally required determinants for ER whorl regulation: residues E95/L92/L96 in the cytoplasmic domain, and K146/V152 in the transmembrane domain. These sites are distinct from the binding sites for established partners Yif1A and Ypt1/Ypt31 Rab GTPases, suggesting Yip1A controls ER membrane organization through a novel binding partner. Yif1A knockdown did not cause ER whorl formation, supporting uncoupling of partner binding from ER organization.","method":"Comprehensive mutagenesis of Yip1A, ER morphology assays, Yif1A knockdown, functional complementation","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — systematic mutagenesis with functional readout, single lab, but no direct identification of the novel binding partner","pmids":["23342155"],"is_preprint":false},{"year":2005,"finding":"Human Yip1A (YIPF5) interacts with human Yif1 (HsYif1) and specifies its localization to the Golgi apparatus. Overexpression of a cytoplasmic domain-deleted mutant of HsYip1A disrupts the Golgi localization of HsYif1.","method":"Yeast two-hybrid, immunoprecipitation pulldown, immunofluorescence co-localization, dominant-negative mutant overexpression","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction confirmed by two-hybrid and Co-IP, localization disruption by dominant-negative mutant, single lab","pmids":["15990086"],"is_preprint":false},{"year":2015,"finding":"Yip1A (YIPF5) is a host factor required for activation of the IRE1 pathway of the unfolded protein response (UPR). Yip1A mediates IRE1 phosphorylation through high-order assembly of IRE1 molecules at ER exit sites (ERES) under UPR conditions. In Yip1A-knockdown cells, Brucella abortus failed to generate ER-derived vacuoles and remained in endosomal/lysosomal compartments.","method":"RNAi knockdown, IRE1 phosphorylation assays, fluorescence and electron microscopy of ER exit sites and vacuole formation, infection experiments","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (knockdown, phosphorylation assay, microscopy, infection model), single lab","pmids":["25742138"],"is_preprint":false},{"year":2017,"finding":"Yip1A (YIPF5) constitutively activates both the IRE1 and PERK pathways of the UPR in HeLa and CaSki cervical cancer cells, mediating IRE1 phosphorylation and PERK transcription, thereby upregulating anti-apoptotic proteins and autophagy-related proteins to promote cancer cell survival. Depletion of Yip1A by RNAi induced apoptotic cell death.","method":"RNAi knockdown, UPR pathway assays (IRE1 phosphorylation, PERK transcription), apoptosis assays, western blotting","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pathway readouts with RNAi knockdown and apoptosis endpoint, single lab","pmids":["28358375"],"is_preprint":false},{"year":2019,"finding":"YIPF5 positively regulates STING-mediated innate immune responses by interacting with both STING and COPII components, facilitating STING recruitment to COPII vesicles and promoting STING trafficking from the ER to the Golgi upon cytoplasmic dsDNA stimulation. Knockdown of YIPF5 impairs type I IFN production in response to DNA viruses.","method":"Co-immunoprecipitation (YIPF5 with STING and COPII components), RNAi knockdown, type I IFN production assays, viral infection assays","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP interaction data plus functional knockdown with IFN readout, single lab","pmids":["31391232"],"is_preprint":false},{"year":2020,"finding":"Loss of YIPF5 function in stem cell-derived islet cells causes proinsulin retention in the ER, marked ER stress, and β cell failure. Partial YIPF5 silencing increases β cell sensitivity to ER stress-induced apoptosis. This establishes YIPF5 as essential for ER-to-Golgi trafficking of proinsulin in β cells.","method":"RNAi silencing in EndoC-βH1 cells, YIPF5 knockout and mutation knockin in embryonic stem cells, patient-derived iPSCs differentiated to islet cells, proinsulin localization by immunofluorescence, ER stress markers, apoptosis assays","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — three independent human β cell model systems (silencing, KO, knockin, patient iPSCs) with multiple orthogonal readouts; replicated across models","pmids":["33164986"],"is_preprint":false},{"year":2023,"finding":"The YIPF5 (p.W218R) mutation causes ER stress in cortical neurons and interferes with generation of apical progenitors (APs) in the developing cortex, leading to primary microcephaly. The mutant rabbit model links YIPF5 loss-of-function to unfolded protein response induction and neurodevelopmental defects.","method":"SpRY-ABEmax base editing to generate knockin rabbits, cortical progenitor analysis, ER stress markers, behavioral and morphological phenotyping","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo knockin animal model with cortical progenitor and ER stress readouts, single lab","pmids":["37142085"],"is_preprint":false},{"year":2025,"finding":"YIPF5 interacts with viral non-structural proteins nsp3, nsp4, and nsp6 and facilitates formation of double-membrane vesicles (DMVs) during PEDV coronavirus infection. YIPF5 knockout suppresses PEDV replication and disrupts the nsp3–nsp4 interaction required for DMV biogenesis.","method":"Whole-genome CRISPR/Cas9 screens, YIPF5 knockout, Co-immunoprecipitation with viral nsps, DMV morphology by electron microscopy, viral replication assays","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-scale screen hit validated by KO and Co-IP with mechanistic DMV readout, single lab","pmids":["40422075"],"is_preprint":false},{"year":2026,"finding":"YIPF5 directly interacts with the ER export receptor SURF4 and negatively regulates SURF4-mediated ER export of a subset of proteins including neuronal adhesion molecules. YIPF5 knockout causes elongated ERGIC53- and Rab1-positive tubules from ER exit sites, alters SURF4 localization, and shifts the cell surface and secretome composition. In utero knockdown of Yipf5 in embryonic mouse brains induces premature neuronal migration and abnormal neuronal morphology.","method":"Co-immunoprecipitation (YIPF5–SURF4 interaction), YIPF5 knockout cells, cell surface proteomics and secretome analysis, live-cell imaging of ERGIC53/Rab1 tubules, kinetic ER export assays, in utero knockdown in mouse embryonic brain","journal":"iScience","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct protein interaction (Co-IP), KO proteomics, morphological assays, and in vivo mouse brain knockdown; multiple orthogonal methods across two publications (peer-reviewed + preprint)","pmids":["41717013"],"is_preprint":false},{"year":2026,"finding":"YIPFα1A (YIPF5) expression is post-transcriptionally regulated by rare-codon enrichment in the CDS (suppressing expression at the mRNA level via translation-coupled mRNA decay) and by the 3' UTR: a proximal segment (51-150) stabilizes mRNA increasing both mRNA and protein levels, while a distal segment (1116-2230) increases mRNA but reduces translation efficiency.","method":"Codon usage analysis, 3' UTR deletion mapping, mRNA and protein quantification, reporter assays","journal":"FEBS open bio","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — deletion mapping and quantification experiments, single lab, no orthogonal mechanistic validation of proposed decay pathway","pmids":["41940818"],"is_preprint":false}],"current_model":"YIPF5 (also known as Yip1A/SMAP-5/FinGER5) is a multi-spanning ER-membrane protein that cycles between the ER and early Golgi, where it regulates ER network organization (preventing concentric whorl formation via E95 and K146 residues), facilitates COPII-mediated anterograde ER-to-Golgi trafficking of specific cargoes including proinsulin, directly interacts with and negatively regulates the ER export receptor SURF4, mediates COPI-independent retrograde Golgi-to-ER transport through Rab6 membrane recruitment, and activates the IRE1 (and PERK) branches of the unfolded protein response through high-order IRE1 assembly at ER exit sites; loss of YIPF5 function causes proinsulin retention and ER stress in β cells, premature neuronal migration and microcephaly in vivo, and impairs STING trafficking to the Golgi during innate immune responses to cytoplasmic DNA."},"narrative":{"mechanistic_narrative":"YIPF5 is a multi-spanning ER/ER-Golgi intermediate compartment membrane protein that organizes the early secretory pathway, coupling ER membrane architecture to COPII-dependent anterograde export and bidirectional ER-Golgi trafficking [PMID:19509059, PMID:20237155]. It is required to maintain a dispersed ER network: its depletion restructures the ER into concentric whorls and slows COPII-mediated cargo export, a function that maps to discrete determinants in its cytoplasmic (E95/L92/L96) and transmembrane (K146/V152) domains that are distinct from the binding sites for its partner Yif1 and Rab GTPases [PMID:20237155, PMID:23342155, PMID:15990086]. On the trafficking side, YIPF5 mediates COPI-independent retrograde Golgi-to-ER transport via Rab6 membrane recruitment [PMID:19509059], and directly binds the ER export receptor SURF4 to negatively regulate SURF4-dependent ER export of a subset of cargoes including neuronal adhesion molecules [PMID:41717013]. YIPF5 also activates the IRE1 (and PERK) branches of the unfolded protein response by promoting high-order IRE1 assembly at ER exit sites, a stress-response output that promotes survival in cancer cells [PMID:25742138, PMID:28358375]. Through these activities YIPF5 supports specific cargo trafficking and innate immune signaling: it facilitates STING recruitment to COPII vesicles and ER-to-Golgi transit during cytoplasmic DNA sensing [PMID:31391232], and is required for ER-to-Golgi trafficking of proinsulin in β cells, where its loss causes proinsulin retention, ER stress, and β cell failure [PMID:33164986]. Loss-of-function and disease-associated mutations link YIPF5 to β cell failure and to primary microcephaly with impaired cortical progenitor generation and premature neuronal migration [PMID:33164986, PMID:37142085, PMID:41717013].","teleology":[{"year":2005,"claim":"Establishing YIPF5's first physical partner addressed whether it functions through a defined binding interaction, showing it determines Golgi localization of Yif1.","evidence":"Yeast two-hybrid, Co-IP, and dominant-negative cytoplasmic-domain mutant in human cells","pmids":["15990086"],"confidence":"Medium","gaps":["Functional consequence of the YIPF5–Yif1 complex for trafficking not defined","No structural detail of the interaction"]},{"year":2009,"claim":"Defined YIPF5's directionality in the secretory pathway by showing it acts in COPI-independent retrograde Golgi-to-ER transport rather than anterograde flux.","evidence":"RNAi knockdown, recombinant N-terminal domain inhibition, Shiga toxin/VSVG transport assays, and Rab6 membrane fractionation","pmids":["19509059"],"confidence":"Medium","gaps":["Mechanism of Rab6 membrane recruitment by YIPF5 not resolved","Direct cargo selectivity for retrograde route not mapped"]},{"year":2010,"claim":"Connected YIPF5 to ER membrane architecture by showing it prevents ER whorl formation and supports COPII export, localizing the function to a single conserved residue.","evidence":"RNAi depletion, live-cell/EM ER morphology, COPII export assays, and E95K site-directed mutagenesis","pmids":["20237155"],"confidence":"High","gaps":["Molecular partner mediating ER dispersal not identified","Link between whorl prevention and export rate left mechanistically implicit"]},{"year":2013,"claim":"Refined the structure-function map by separating ER-organization determinants from known partner-binding sites, implying a novel unidentified effector.","evidence":"Comprehensive mutagenesis with ER morphology readouts and Yif1A knockdown controls","pmids":["23342155"],"confidence":"Medium","gaps":["The hypothesized novel binding partner was never identified","Whether transmembrane (K146/V152) and cytoplasmic (E95) determinants act in the same pathway is unresolved"]},{"year":2015,"claim":"Identified YIPF5 as an activator of the UPR by showing it drives high-order IRE1 assembly at ER exit sites, linking secretory-pathway architecture to stress signaling.","evidence":"RNAi knockdown, IRE1 phosphorylation assays, ERES microscopy, and Brucella vacuole-formation infection model","pmids":["25742138"],"confidence":"Medium","gaps":["Whether YIPF5 directly contacts IRE1 versus scaffolds ERES is unclear","Physiological trigger that engages this function not defined"]},{"year":2017,"claim":"Extended UPR control to constitutive activation of both IRE1 and PERK that sustains cancer cell survival, framing YIPF5 as a pro-survival node.","evidence":"RNAi knockdown with IRE1/PERK pathway readouts and apoptosis assays in cervical cancer cells","pmids":["28358375"],"confidence":"Medium","gaps":["Mechanism of PERK arm engagement distinct from IRE1 not dissected","Generality beyond cervical cancer lines untested"]},{"year":2019,"claim":"Placed YIPF5 in innate immunity by showing it bridges STING to COPII vesicles to drive STING ER-to-Golgi trafficking and type I IFN.","evidence":"Co-IP of YIPF5 with STING and COPII components, RNAi knockdown, and IFN/viral infection assays","pmids":["31391232"],"confidence":"Medium","gaps":["Whether STING is a direct cargo of YIPF5-assisted COPII selection is not established","Reciprocal interaction validation limited"]},{"year":2020,"claim":"Demonstrated cargo-specific physiological importance by showing YIPF5 is essential for proinsulin ER-to-Golgi trafficking, with loss causing β cell ER stress and failure.","evidence":"RNAi silencing, KO/knockin embryonic stem cells, and patient-derived iPSC islet cells with proinsulin localization and ER stress/apoptosis readouts","pmids":["33164986"],"confidence":"High","gaps":["Whether proinsulin export depends on the SURF4 or COPII activities of YIPF5 not resolved here","Mechanism linking trafficking defect to UPR amplitude not fully dissected"]},{"year":2023,"claim":"Linked a specific YIPF5 mutation to neurodevelopment by showing p.W218R induces neuronal ER stress and impairs apical progenitor generation, causing microcephaly.","evidence":"Base-edited knockin rabbit model with cortical progenitor analysis and ER stress markers","pmids":["37142085"],"confidence":"Medium","gaps":["How the mutation alters specific YIPF5 trafficking functions is not defined","Cell-type-specific cargo defects in neurons not identified"]},{"year":2026,"claim":"Identified SURF4 as a direct partner and revealed YIPF5 as a negative regulator of SURF4-mediated ER export, connecting it to neuronal surface composition and migration in vivo.","evidence":"Co-IP, KO cell surface proteomics/secretome, ERGIC53/Rab1 tubule imaging, kinetic export assays, and in utero mouse brain knockdown","pmids":["41717013"],"confidence":"High","gaps":["Structural basis of YIPF5–SURF4 antagonism not solved","Full cargo repertoire under YIPF5/SURF4 control incomplete"]},{"year":2025,"claim":"Showed YIPF5 is hijacked by coronaviruses, interacting with nsp3/nsp4/nsp6 to support double-membrane vesicle biogenesis required for replication.","evidence":"Genome-wide CRISPR screen, KO, Co-IP with viral nsps, and DMV electron microscopy with replication assays","pmids":["40422075"],"confidence":"Medium","gaps":["Whether DMV support reflects normal ER-membrane organizing activity is unclear","Direct versus indirect nsp interactions not distinguished"]},{"year":2026,"claim":"Characterized post-transcriptional control of YIPF5 levels via rare-codon-coupled mRNA decay and 3' UTR elements, addressing how its abundance is tuned.","evidence":"Codon usage analysis, 3' UTR deletion mapping, and mRNA/protein reporter quantification","pmids":["41940818"],"confidence":"Medium","gaps":["Translation-coupled decay pathway not orthogonally validated","Physiological conditions regulating these elements unknown"]},{"year":null,"claim":"The identity of the effector mediating YIPF5-dependent ER membrane dispersal, and how its trafficking, ER-organization, and UPR-activating functions are mechanistically integrated, remain unresolved.","evidence":"No timeline discovery identifies the novel partner predicted by the structure-function mapping or unifies the distinct activities","pmids":[],"confidence":"Medium","gaps":["Novel ER-organization binding partner unidentified","No structural model of YIPF5 or its complexes","Whether retrograde, anterograde-regulatory, and UPR roles share one biochemical mechanism is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,6,10]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,5,10]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,1,7,10]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[0,3,6]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,1,7,10]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[4,5]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[6,7,10]}],"complexes":[],"partners":["YIF1A","SURF4","RAB6","STING1","IRE1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q969M3","full_name":"Protein YIPF5","aliases":["Five-pass transmembrane protein localizing in the Golgi apparatus and the endoplasmic reticulum 5","Smooth muscle cell-associated protein 5","SMAP-5","YIP1 family member 5","YPT-interacting protein 1 A"],"length_aa":257,"mass_kda":28.0,"function":"Plays a role in transport between endoplasmic reticulum and Golgi. In pancreatic beta cells, required to transport proinsulin from endoplasmic reticulum into the Golgi (PubMed:33164986)","subcellular_location":"Endoplasmic reticulum membrane; Golgi apparatus, cis-Golgi network membrane; Cytoplasmic vesicle, COPII-coated vesicle","url":"https://www.uniprot.org/uniprotkb/Q969M3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/YIPF5","classification":"Not Classified","n_dependent_lines":120,"n_total_lines":1208,"dependency_fraction":0.09933774834437085},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000145817","cell_line_id":"CID000896","localizations":[{"compartment":"golgi","grade":3},{"compartment":"vesicles","grade":3},{"compartment":"er","grade":2}],"interactors":[{"gene":"RABAC1","stoichiometry":10.0},{"gene":"LMAN2","stoichiometry":10.0},{"gene":"YIF1A","stoichiometry":10.0},{"gene":"IER3IP1","stoichiometry":10.0},{"gene":"YIF1B","stoichiometry":10.0},{"gene":"RAB1B","stoichiometry":4.0},{"gene":"RAB2A","stoichiometry":4.0},{"gene":"CYB5R3","stoichiometry":0.2},{"gene":"SEC24B","stoichiometry":0.2},{"gene":"EI24","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000896","total_profiled":1310},"omim":[{"mim_id":"619278","title":"MICROCEPHALY, EPILEPSY, AND DIABETES SYNDROME 2; MEDS2","url":"https://www.omim.org/entry/619278"},{"mim_id":"614231","title":"MICROCEPHALY, EPILEPSY, AND DIABETES SYNDROME 1; MEDS1","url":"https://www.omim.org/entry/614231"},{"mim_id":"612374","title":"STIMULATOR OF INTERFERON RESPONSE cGAMP INTERACTOR 1; STING1","url":"https://www.omim.org/entry/612374"},{"mim_id":"611484","title":"YIP1-INTERACTING FACTOR HOMOLOG A, MEMBRANE-TRAFFICKING PROTEIN; YIF1A","url":"https://www.omim.org/entry/611484"},{"mim_id":"611483","title":"YIP1 DOMAIN FAMILY, MEMBER 5; YIPF5","url":"https://www.omim.org/entry/611483"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endoplasmic reticulum","reliability":"Supported"},{"location":"Golgi apparatus","reliability":"Supported"},{"location":"Vesicles","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/YIPF5"},"hgnc":{"alias_symbol":["SMAP-5","FinGER5","Yip1a","YIPFalpha1A"],"prev_symbol":[]},"alphafold":{"accession":"Q969M3","domains":[{"cath_id":"-","chopping":"119-255","consensus_level":"high","plddt":86.1404,"start":119,"end":255}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q969M3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q969M3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q969M3-F1-predicted_aligned_error_v6.png","plddt_mean":67.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=YIPF5","jax_strain_url":"https://www.jax.org/strain/search?query=YIPF5"},"sequence":{"accession":"Q969M3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q969M3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q969M3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q969M3"}},"corpus_meta":[{"pmid":"33164986","id":"PMC_33164986","title":"YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress.","date":"2020","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/33164986","citation_count":74,"is_preprint":false},{"pmid":"25742138","id":"PMC_25742138","title":"Yip1A, a novel host factor for the activation of the IRE1 pathway of the unfolded protein response during Brucella infection.","date":"2015","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/25742138","citation_count":63,"is_preprint":false},{"pmid":"31391232","id":"PMC_31391232","title":"YIPF5 Is Essential for Innate Immunity to DNA Virus and Facilitates COPII-Dependent STING Trafficking.","date":"2019","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/31391232","citation_count":54,"is_preprint":false},{"pmid":"19509059","id":"PMC_19509059","title":"Yip1A regulates the COPI-independent retrograde transport from the Golgi complex to the ER.","date":"2009","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/19509059","citation_count":39,"is_preprint":false},{"pmid":"20237155","id":"PMC_20237155","title":"Yip1A structures the mammalian endoplasmic reticulum.","date":"2010","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/20237155","citation_count":34,"is_preprint":false},{"pmid":"15922870","id":"PMC_15922870","title":"Cloning, cellular localization, genomic organization, and tissue-specific expression of the TGFbeta1-inducible SMAP-5 gene.","date":"2005","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/15922870","citation_count":28,"is_preprint":false},{"pmid":"28358375","id":"PMC_28358375","title":"Novel prosurvival function of Yip1A in human cervical cancer cells: constitutive activation of the IRE1 and PERK pathways of the unfolded protein response.","date":"2017","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/28358375","citation_count":21,"is_preprint":false},{"pmid":"15990086","id":"PMC_15990086","title":"Human Yip1A specifies the localization of Yif1 to the Golgi apparatus.","date":"2005","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/15990086","citation_count":19,"is_preprint":false},{"pmid":"36916000","id":"PMC_36916000","title":"Vitamin D receptor (VDR) mediates the quiescence of activated hepatic stellate cells (aHSCs) by regulating M2 macrophage exosomal smooth muscle cell-associated protein 5 (SMAP-5).","date":"2023","source":"Journal of Zhejiang University. 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Knockdown delayed Shiga toxin transport from Golgi to ER but did not affect anterograde VSVGts045 transport. The N-terminal cytoplasmic domain of Yip1A inhibited COPI-independent retrograde transport of GT-GFP. Yip1A knockdown also caused dissociation of Rab6 from membranes.\",\n      \"method\": \"RNAi knockdown, recombinant N-terminal domain inhibition assay, intracellular transport assays, immunofluorescence, membrane fractionation\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple transport assays with specific cargo readouts, single lab, orthogonal methods (RNAi + recombinant domain inhibition + Rab6 membrane recruitment)\",\n      \"pmids\": [\"19509059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Yip1A (YIPF5) is required for ER network dispersal; depletion causes restructuring of the ER into concentric whorls and markedly slows COPII-mediated protein export. A single conserved amino acid substitution (E95K) in the N-terminal cytoplasmic domain blocks the ER network dispersal function of Yip1A.\",\n      \"method\": \"RNAi depletion, live-cell and electron microscopy of ER morphology, COPII cargo export assays, site-directed mutagenesis (E95K)\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — active-site mutagenesis (E95K) combined with morphological and functional export assays; multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"20237155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Mutational analysis of Yip1A identified two discrete functionally required determinants for ER whorl regulation: residues E95/L92/L96 in the cytoplasmic domain, and K146/V152 in the transmembrane domain. These sites are distinct from the binding sites for established partners Yif1A and Ypt1/Ypt31 Rab GTPases, suggesting Yip1A controls ER membrane organization through a novel binding partner. Yif1A knockdown did not cause ER whorl formation, supporting uncoupling of partner binding from ER organization.\",\n      \"method\": \"Comprehensive mutagenesis of Yip1A, ER morphology assays, Yif1A knockdown, functional complementation\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic mutagenesis with functional readout, single lab, but no direct identification of the novel binding partner\",\n      \"pmids\": [\"23342155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Human Yip1A (YIPF5) interacts with human Yif1 (HsYif1) and specifies its localization to the Golgi apparatus. Overexpression of a cytoplasmic domain-deleted mutant of HsYip1A disrupts the Golgi localization of HsYif1.\",\n      \"method\": \"Yeast two-hybrid, immunoprecipitation pulldown, immunofluorescence co-localization, dominant-negative mutant overexpression\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction confirmed by two-hybrid and Co-IP, localization disruption by dominant-negative mutant, single lab\",\n      \"pmids\": [\"15990086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Yip1A (YIPF5) is a host factor required for activation of the IRE1 pathway of the unfolded protein response (UPR). Yip1A mediates IRE1 phosphorylation through high-order assembly of IRE1 molecules at ER exit sites (ERES) under UPR conditions. In Yip1A-knockdown cells, Brucella abortus failed to generate ER-derived vacuoles and remained in endosomal/lysosomal compartments.\",\n      \"method\": \"RNAi knockdown, IRE1 phosphorylation assays, fluorescence and electron microscopy of ER exit sites and vacuole formation, infection experiments\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (knockdown, phosphorylation assay, microscopy, infection model), single lab\",\n      \"pmids\": [\"25742138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Yip1A (YIPF5) constitutively activates both the IRE1 and PERK pathways of the UPR in HeLa and CaSki cervical cancer cells, mediating IRE1 phosphorylation and PERK transcription, thereby upregulating anti-apoptotic proteins and autophagy-related proteins to promote cancer cell survival. Depletion of Yip1A by RNAi induced apoptotic cell death.\",\n      \"method\": \"RNAi knockdown, UPR pathway assays (IRE1 phosphorylation, PERK transcription), apoptosis assays, western blotting\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pathway readouts with RNAi knockdown and apoptosis endpoint, single lab\",\n      \"pmids\": [\"28358375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"YIPF5 positively regulates STING-mediated innate immune responses by interacting with both STING and COPII components, facilitating STING recruitment to COPII vesicles and promoting STING trafficking from the ER to the Golgi upon cytoplasmic dsDNA stimulation. Knockdown of YIPF5 impairs type I IFN production in response to DNA viruses.\",\n      \"method\": \"Co-immunoprecipitation (YIPF5 with STING and COPII components), RNAi knockdown, type I IFN production assays, viral infection assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP interaction data plus functional knockdown with IFN readout, single lab\",\n      \"pmids\": [\"31391232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Loss of YIPF5 function in stem cell-derived islet cells causes proinsulin retention in the ER, marked ER stress, and β cell failure. Partial YIPF5 silencing increases β cell sensitivity to ER stress-induced apoptosis. This establishes YIPF5 as essential for ER-to-Golgi trafficking of proinsulin in β cells.\",\n      \"method\": \"RNAi silencing in EndoC-βH1 cells, YIPF5 knockout and mutation knockin in embryonic stem cells, patient-derived iPSCs differentiated to islet cells, proinsulin localization by immunofluorescence, ER stress markers, apoptosis assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — three independent human β cell model systems (silencing, KO, knockin, patient iPSCs) with multiple orthogonal readouts; replicated across models\",\n      \"pmids\": [\"33164986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The YIPF5 (p.W218R) mutation causes ER stress in cortical neurons and interferes with generation of apical progenitors (APs) in the developing cortex, leading to primary microcephaly. The mutant rabbit model links YIPF5 loss-of-function to unfolded protein response induction and neurodevelopmental defects.\",\n      \"method\": \"SpRY-ABEmax base editing to generate knockin rabbits, cortical progenitor analysis, ER stress markers, behavioral and morphological phenotyping\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockin animal model with cortical progenitor and ER stress readouts, single lab\",\n      \"pmids\": [\"37142085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"YIPF5 interacts with viral non-structural proteins nsp3, nsp4, and nsp6 and facilitates formation of double-membrane vesicles (DMVs) during PEDV coronavirus infection. YIPF5 knockout suppresses PEDV replication and disrupts the nsp3–nsp4 interaction required for DMV biogenesis.\",\n      \"method\": \"Whole-genome CRISPR/Cas9 screens, YIPF5 knockout, Co-immunoprecipitation with viral nsps, DMV morphology by electron microscopy, viral replication assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-scale screen hit validated by KO and Co-IP with mechanistic DMV readout, single lab\",\n      \"pmids\": [\"40422075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"YIPF5 directly interacts with the ER export receptor SURF4 and negatively regulates SURF4-mediated ER export of a subset of proteins including neuronal adhesion molecules. YIPF5 knockout causes elongated ERGIC53- and Rab1-positive tubules from ER exit sites, alters SURF4 localization, and shifts the cell surface and secretome composition. In utero knockdown of Yipf5 in embryonic mouse brains induces premature neuronal migration and abnormal neuronal morphology.\",\n      \"method\": \"Co-immunoprecipitation (YIPF5–SURF4 interaction), YIPF5 knockout cells, cell surface proteomics and secretome analysis, live-cell imaging of ERGIC53/Rab1 tubules, kinetic ER export assays, in utero knockdown in mouse embryonic brain\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct protein interaction (Co-IP), KO proteomics, morphological assays, and in vivo mouse brain knockdown; multiple orthogonal methods across two publications (peer-reviewed + preprint)\",\n      \"pmids\": [\"41717013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"YIPFα1A (YIPF5) expression is post-transcriptionally regulated by rare-codon enrichment in the CDS (suppressing expression at the mRNA level via translation-coupled mRNA decay) and by the 3' UTR: a proximal segment (51-150) stabilizes mRNA increasing both mRNA and protein levels, while a distal segment (1116-2230) increases mRNA but reduces translation efficiency.\",\n      \"method\": \"Codon usage analysis, 3' UTR deletion mapping, mRNA and protein quantification, reporter assays\",\n      \"journal\": \"FEBS open bio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — deletion mapping and quantification experiments, single lab, no orthogonal mechanistic validation of proposed decay pathway\",\n      \"pmids\": [\"41940818\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"YIPF5 (also known as Yip1A/SMAP-5/FinGER5) is a multi-spanning ER-membrane protein that cycles between the ER and early Golgi, where it regulates ER network organization (preventing concentric whorl formation via E95 and K146 residues), facilitates COPII-mediated anterograde ER-to-Golgi trafficking of specific cargoes including proinsulin, directly interacts with and negatively regulates the ER export receptor SURF4, mediates COPI-independent retrograde Golgi-to-ER transport through Rab6 membrane recruitment, and activates the IRE1 (and PERK) branches of the unfolded protein response through high-order IRE1 assembly at ER exit sites; loss of YIPF5 function causes proinsulin retention and ER stress in β cells, premature neuronal migration and microcephaly in vivo, and impairs STING trafficking to the Golgi during innate immune responses to cytoplasmic DNA.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"YIPF5 is a multi-spanning ER/ER-Golgi intermediate compartment membrane protein that organizes the early secretory pathway, coupling ER membrane architecture to COPII-dependent anterograde export and bidirectional ER-Golgi trafficking [#0, #1]. It is required to maintain a dispersed ER network: its depletion restructures the ER into concentric whorls and slows COPII-mediated cargo export, a function that maps to discrete determinants in its cytoplasmic (E95/L92/L96) and transmembrane (K146/V152) domains that are distinct from the binding sites for its partner Yif1 and Rab GTPases [#1, #2, #3]. On the trafficking side, YIPF5 mediates COPI-independent retrograde Golgi-to-ER transport via Rab6 membrane recruitment [#0], and directly binds the ER export receptor SURF4 to negatively regulate SURF4-dependent ER export of a subset of cargoes including neuronal adhesion molecules [#10]. YIPF5 also activates the IRE1 (and PERK) branches of the unfolded protein response by promoting high-order IRE1 assembly at ER exit sites, a stress-response output that promotes survival in cancer cells [#4, #5]. Through these activities YIPF5 supports specific cargo trafficking and innate immune signaling: it facilitates STING recruitment to COPII vesicles and ER-to-Golgi transit during cytoplasmic DNA sensing [#6], and is required for ER-to-Golgi trafficking of proinsulin in \\u03b2 cells, where its loss causes proinsulin retention, ER stress, and \\u03b2 cell failure [#7]. Loss-of-function and disease-associated mutations link YIPF5 to \\u03b2 cell failure and to primary microcephaly with impaired cortical progenitor generation and premature neuronal migration [#7, #8, #10].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Establishing YIPF5's first physical partner addressed whether it functions through a defined binding interaction, showing it determines Golgi localization of Yif1.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, and dominant-negative cytoplasmic-domain mutant in human cells\",\n      \"pmids\": [\"15990086\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the YIPF5\\u2013Yif1 complex for trafficking not defined\", \"No structural detail of the interaction\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined YIPF5's directionality in the secretory pathway by showing it acts in COPI-independent retrograde Golgi-to-ER transport rather than anterograde flux.\",\n      \"evidence\": \"RNAi knockdown, recombinant N-terminal domain inhibition, Shiga toxin/VSVG transport assays, and Rab6 membrane fractionation\",\n      \"pmids\": [\"19509059\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of Rab6 membrane recruitment by YIPF5 not resolved\", \"Direct cargo selectivity for retrograde route not mapped\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connected YIPF5 to ER membrane architecture by showing it prevents ER whorl formation and supports COPII export, localizing the function to a single conserved residue.\",\n      \"evidence\": \"RNAi depletion, live-cell/EM ER morphology, COPII export assays, and E95K site-directed mutagenesis\",\n      \"pmids\": [\"20237155\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular partner mediating ER dispersal not identified\", \"Link between whorl prevention and export rate left mechanistically implicit\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Refined the structure-function map by separating ER-organization determinants from known partner-binding sites, implying a novel unidentified effector.\",\n      \"evidence\": \"Comprehensive mutagenesis with ER morphology readouts and Yif1A knockdown controls\",\n      \"pmids\": [\"23342155\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The hypothesized novel binding partner was never identified\", \"Whether transmembrane (K146/V152) and cytoplasmic (E95) determinants act in the same pathway is unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified YIPF5 as an activator of the UPR by showing it drives high-order IRE1 assembly at ER exit sites, linking secretory-pathway architecture to stress signaling.\",\n      \"evidence\": \"RNAi knockdown, IRE1 phosphorylation assays, ERES microscopy, and Brucella vacuole-formation infection model\",\n      \"pmids\": [\"25742138\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether YIPF5 directly contacts IRE1 versus scaffolds ERES is unclear\", \"Physiological trigger that engages this function not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended UPR control to constitutive activation of both IRE1 and PERK that sustains cancer cell survival, framing YIPF5 as a pro-survival node.\",\n      \"evidence\": \"RNAi knockdown with IRE1/PERK pathway readouts and apoptosis assays in cervical cancer cells\",\n      \"pmids\": [\"28358375\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of PERK arm engagement distinct from IRE1 not dissected\", \"Generality beyond cervical cancer lines untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed YIPF5 in innate immunity by showing it bridges STING to COPII vesicles to drive STING ER-to-Golgi trafficking and type I IFN.\",\n      \"evidence\": \"Co-IP of YIPF5 with STING and COPII components, RNAi knockdown, and IFN/viral infection assays\",\n      \"pmids\": [\"31391232\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether STING is a direct cargo of YIPF5-assisted COPII selection is not established\", \"Reciprocal interaction validation limited\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated cargo-specific physiological importance by showing YIPF5 is essential for proinsulin ER-to-Golgi trafficking, with loss causing \\u03b2 cell ER stress and failure.\",\n      \"evidence\": \"RNAi silencing, KO/knockin embryonic stem cells, and patient-derived iPSC islet cells with proinsulin localization and ER stress/apoptosis readouts\",\n      \"pmids\": [\"33164986\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether proinsulin export depends on the SURF4 or COPII activities of YIPF5 not resolved here\", \"Mechanism linking trafficking defect to UPR amplitude not fully dissected\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked a specific YIPF5 mutation to neurodevelopment by showing p.W218R induces neuronal ER stress and impairs apical progenitor generation, causing microcephaly.\",\n      \"evidence\": \"Base-edited knockin rabbit model with cortical progenitor analysis and ER stress markers\",\n      \"pmids\": [\"37142085\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How the mutation alters specific YIPF5 trafficking functions is not defined\", \"Cell-type-specific cargo defects in neurons not identified\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified SURF4 as a direct partner and revealed YIPF5 as a negative regulator of SURF4-mediated ER export, connecting it to neuronal surface composition and migration in vivo.\",\n      \"evidence\": \"Co-IP, KO cell surface proteomics/secretome, ERGIC53/Rab1 tubule imaging, kinetic export assays, and in utero mouse brain knockdown\",\n      \"pmids\": [\"41717013\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of YIPF5\\u2013SURF4 antagonism not solved\", \"Full cargo repertoire under YIPF5/SURF4 control incomplete\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed YIPF5 is hijacked by coronaviruses, interacting with nsp3/nsp4/nsp6 to support double-membrane vesicle biogenesis required for replication.\",\n      \"evidence\": \"Genome-wide CRISPR screen, KO, Co-IP with viral nsps, and DMV electron microscopy with replication assays\",\n      \"pmids\": [\"40422075\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether DMV support reflects normal ER-membrane organizing activity is unclear\", \"Direct versus indirect nsp interactions not distinguished\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Characterized post-transcriptional control of YIPF5 levels via rare-codon-coupled mRNA decay and 3' UTR elements, addressing how its abundance is tuned.\",\n      \"evidence\": \"Codon usage analysis, 3' UTR deletion mapping, and mRNA/protein reporter quantification\",\n      \"pmids\": [\"41940818\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Translation-coupled decay pathway not orthogonally validated\", \"Physiological conditions regulating these elements unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The identity of the effector mediating YIPF5-dependent ER membrane dispersal, and how its trafficking, ER-organization, and UPR-activating functions are mechanistically integrated, remain unresolved.\",\n      \"evidence\": \"No timeline discovery identifies the novel partner predicted by the structure-function mapping or unifies the distinct activities\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Novel ER-organization binding partner unidentified\", \"No structural model of YIPF5 or its complexes\", \"Whether retrograde, anterograde-regulatory, and UPR roles share one biochemical mechanism is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 6, 10]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 5, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 1, 7, 10]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [0, 3, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 1, 7, 10]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [6, 7, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"YIF1A\", \"SURF4\", \"RAB6\", \"STING1\", \"IRE1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}