{"gene":"YIPF6","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2012,"finding":"YIPF6 is a five transmembrane-spanning protein associated with Golgi compartments; null mutation (Klein-Zschocher) causes defective formation and secretion of large secretory granules from Paneth and goblet cells, leading to spontaneous intestinal inflammation, establishing YIPF6 as required for secretory granule biogenesis in intestinal epithelial cells.","method":"Forward genetic screen, electron microscopy, immunocytochemistry, gene expression analysis, DSS colitis model in Yipf6 null mice","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (EM, immunocytochemistry, in vivo genetics) in a well-controlled loss-of-function study, establishing specific cellular phenotype","pmids":["22802641"],"is_preprint":false},{"year":2019,"finding":"YIPF6 binds FGF21 in the endoplasmic reticulum and controls its packaging into COPII vesicles, thereby limiting FGF21 secretion; loss of YIPF6 function increases FGF21 plasma levels and confers resistance to diet-induced obesity in mice.","method":"Co-immunoprecipitation (YIPF6–FGF21 binding in ER), hepatocyte-specific FGF21 deletion epistasis, COPII vesicle sorting assay, plasma FGF21 measurement in Yipf6 mutant mice on high-fat diet","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding assay plus genetic epistasis (hepatocyte-specific FGF21 KO rescues obesity protection), multiple orthogonal methods in one study","pmids":["31289229"],"is_preprint":false},{"year":2017,"finding":"YIPF6 localizes to the Golgi apparatus and its overexpression in 22Rv1 prostate cancer cells reduces cell proliferation and colony formation while enhancing extracellular vesicle (EV) secretion; EVs from YIPF6-overexpressing cells are enriched for coagulation proteins and decrease activated partial thromboplastin time.","method":"Immunohistochemistry, confocal microscopy, siRNA knockdown and stable overexpression, cell proliferation/colony assays, EV isolation by size-exclusion chromatography, LC-MS/MS proteomics, APTT coagulation assay","journal":"The Prostate","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays in a single lab; Golgi localization confirmed by imaging; functional consequences of OE established but mechanistic pathway not fully resolved","pmids":["28144969"],"is_preprint":false},{"year":2016,"finding":"YIPF6 localizes broadly throughout the Golgi stack (both cis and trans compartments); its cytosol-facing N-terminal region and lumen-facing C-terminus define a five-transmembrane topology shared across YIPF family members; RNAi depletion of YIPF6 causes specific morphological changes to the Golgi.","method":"Fluorescence microscopy, membrane topology assays, RNAi knockdown with Golgi morphology readout in mammalian cells","journal":"Histochemistry and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization with functional consequence (Golgi morphology), topology determined experimentally, single lab with two orthogonal methods","pmids":["27999994"],"is_preprint":false},{"year":2017,"finding":"YIPF6 forms stable complexes with YIPF1 and YIPF2 at the medial-/trans-Golgi and TGN; knockdown of YIPF6 reduces protein levels of YIPF1 and YIPF2, indicating YIPF6 is required for the stable expression and Golgi localization of its partners. Free YIPF6 (after dissociating from YIPF1/YIPF2) interferes with Golgi reassembly post-BFA treatment.","method":"Co-immunoprecipitation, immunofluorescence, BFA treatment/washout assay, siRNA knockdown with western blot and immunofluorescence readouts","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and functional knockdown with multiple readouts, single lab","pmids":["28286305"],"is_preprint":false},{"year":2023,"finding":"TVP23B physically interacts with YIPF6 at the Golgi; both proteins are required for intestinal homeostasis and their deficiency results in a common loss of glycosylation enzymes from the Golgi proteome of colonocytes, linking YIPF6 to glycosylation enzyme trafficking.","method":"Forward genetic screen, co-immunoprecipitation (TVP23B–YIPF6 interaction), Golgi proteomics of TVP23B- and YIPF6-deficient colonocytes, in vivo colitis models","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — binding interaction established by co-IP, proteomics provides mechanistic insight; single lab but orthogonal methods","pmids":["37339972"],"is_preprint":false},{"year":2006,"finding":"Yeast Yip4 (ortholog of YIPF6) resides in Tlg2-containing Golgi/endosome compartments and participates in a protein interaction network with Tvp23, Tvp18, and Tvp15; disruption of tvp15 or tvp23 shows synthetic aggravation with ypt6 or ric1 null mutations, placing Yip4 in the late Golgi/endosomal maintenance pathway.","method":"Immunofluorescence, immunoprecipitation of yeast Tvp proteins, genetic epistasis (double-mutant analysis), carboxypeptidase Y and alkaline phosphatase processing assays","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and genetic epistasis in yeast ortholog, single lab; pathway placement supported by multiple methods","pmids":["17178117"],"is_preprint":false},{"year":2018,"finding":"Plant TGNap1 binds YIP4 (plant ortholog of YIPF6) and Rab6, and together these interactions contribute to microtubule-dependent biogenesis and function of a TGN subset, placing YIP4 in a Rab6/microtubule-dependent TGN trafficking pathway.","method":"Co-immunoprecipitation, live-cell imaging, genetic/RNAi loss-of-function in Arabidopsis","journal":"Nature communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — findings are in plants (Arabidopsis), which is an ortholog but with potentially divergent function; single lab, binding shown but mechanistic role of YIP4 specifically not dissected in isolation","pmids":["30552321"],"is_preprint":false}],"current_model":"YIPF6 is a five-transmembrane Golgi-resident protein that forms stable complexes with YIPF1 and YIPF2 to support their expression and Golgi localization; it controls secretory granule biogenesis in intestinal Paneth and goblet cells, regulates FGF21 secretion by binding FGF21 in the ER and directing its packaging into COPII vesicles, interacts with the trans-Golgi protein TVP23B to maintain glycosylation enzyme trafficking, and modulates extracellular vesicle secretion, collectively placing YIPF6 as a key regulator of ER-to-Golgi cargo sorting and post-Golgi secretory pathway homeostasis."},"narrative":{"mechanistic_narrative":"YIPF6 is a five-transmembrane Golgi-resident protein that functions as a regulator of ER-to-Golgi cargo sorting and secretory pathway homeostasis, with a defining requirement in intestinal epithelial secretion [PMID:22802641, PMID:27999994]. Loss of YIPF6 in mice causes defective formation and secretion of large secretory granules from Paneth and goblet cells, producing spontaneous intestinal inflammation [PMID:22802641]. The protein spans the Golgi stack across both cis and trans compartments, with a cytosol-facing N-terminus and a lumen-facing C-terminus, and its depletion alters Golgi morphology [PMID:27999994]. YIPF6 assembles into a stable complex with YIPF1 and YIPF2 at the medial/trans-Golgi and TGN, and is required for the stable expression and Golgi localization of these partners [PMID:28286305]. It also interacts with the trans-Golgi protein TVP23B, and loss of either protein depletes glycosylation enzymes from the colonocyte Golgi proteome, linking YIPF6 to glycosylation enzyme trafficking and intestinal homeostasis [PMID:37339972]. In a distinct secretory role, YIPF6 binds FGF21 in the ER and controls its packaging into COPII vesicles, thereby limiting FGF21 secretion; its loss raises plasma FGF21 and confers resistance to diet-induced obesity [PMID:31289229]. YIPF6 additionally modulates extracellular vesicle secretion in prostate cancer cells [PMID:28144969].","teleology":[{"year":2006,"claim":"Establishing where the YIPF6 ortholog acts placed the protein in the late Golgi/endosomal maintenance machinery rather than the early secretory pathway.","evidence":"Immunoprecipitation and genetic epistasis of yeast Yip4 with Tvp and Ypt6/Ric1 components","pmids":["17178117"],"confidence":"Medium","gaps":["Yeast pathway placement may not transfer to mammalian YIPF6","Direct cargo or molecular activity of Yip4 not defined"]},{"year":2012,"claim":"A forward-genetic loss-of-function model answered what YIPF6 does at the organismal level, revealing an essential role in secretory granule biogenesis in intestinal epithelium.","evidence":"Forward genetic screen, EM, immunocytochemistry and DSS colitis in Yipf6-null mice","pmids":["22802641"],"confidence":"High","gaps":["Molecular mechanism linking YIPF6 to granule formation unresolved","No biochemical partners identified in this study"]},{"year":2016,"claim":"Defining membrane topology and localization clarified how YIPF6 is positioned in the Golgi and that it is needed for Golgi structural integrity.","evidence":"Fluorescence microscopy, membrane topology assays and RNAi with Golgi morphology readout in mammalian cells","pmids":["27999994"],"confidence":"Medium","gaps":["Topology does not reveal catalytic or binding function","Mechanism connecting depletion to morphology change unknown"]},{"year":2017,"claim":"Identifying YIPF1/YIPF2 as stable partners showed YIPF6 acts within a Golgi YIP-family complex whose member stability it controls.","evidence":"Reciprocal co-IP, immunofluorescence, BFA washout and siRNA knockdown in mammalian cells","pmids":["28286305"],"confidence":"Medium","gaps":["Function of the YIPF1/2/6 complex in cargo sorting not defined","Single-lab interaction data"]},{"year":2017,"claim":"Overexpression studies in cancer cells linked YIPF6 to extracellular vesicle output and proliferation control, extending its role to post-Golgi secretion.","evidence":"siRNA/overexpression, EV isolation, LC-MS/MS proteomics and APTT assay in 22Rv1 prostate cancer cells","pmids":["28144969"],"confidence":"Medium","gaps":["Overexpression phenotype may not reflect endogenous function","Mechanism connecting YIPF6 to EV biogenesis unresolved"]},{"year":2019,"claim":"A direct ER cargo-binding role was established, showing YIPF6 gates FGF21 entry into COPII vesicles and thereby controls a metabolic secretory output.","evidence":"Co-IP of ER YIPF6–FGF21 binding, COPII sorting assay, hepatocyte FGF21-KO epistasis and plasma FGF21 in Yipf6-mutant mice on high-fat diet","pmids":["31289229"],"confidence":"High","gaps":["Whether YIPF6 selects other COPII cargoes is unknown","Structural basis of FGF21 recognition not defined"]},{"year":2023,"claim":"The TVP23B interaction tied YIPF6 mechanistically to maintenance of Golgi glycosylation enzymes, explaining part of its intestinal homeostasis function.","evidence":"Forward genetic screen, co-IP and Golgi proteomics of TVP23B- and YIPF6-deficient colonocytes with in vivo colitis models","pmids":["37339972"],"confidence":"Medium","gaps":["How the YIPF6–TVP23B complex retains glycosyltransferases is unclear","Direct enzyme cargo not identified"]},{"year":null,"claim":"The unifying molecular activity of YIPF6 — how a single Golgi YIP-family protein coordinates COPII cargo selection, complex-member stabilization, and glycosylation-enzyme retention — remains undefined.","evidence":"No reconstituted biochemical or structural study of YIPF6 in the corpus","pmids":[],"confidence":"Low","gaps":["No structure of YIPF6 or its complexes","No defined biochemical activity beyond cargo/partner binding","Relationship between ER FGF21 binding and Golgi complex roles not integrated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[1]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[0,2,3,4,5]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[1,5]}],"complexes":["YIPF1-YIPF2-YIPF6 Golgi complex"],"partners":["YIPF1","YIPF2","FGF21","TVP23B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96EC8","full_name":"Protein YIPF6","aliases":["YIP1 family member 6"],"length_aa":236,"mass_kda":26.3,"function":"May be required for stable YIPF1 and YIPF2 protein expression","subcellular_location":"Golgi apparatus membrane","url":"https://www.uniprot.org/uniprotkb/Q96EC8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/YIPF6","classification":"Not Classified","n_dependent_lines":21,"n_total_lines":1208,"dependency_fraction":0.0173841059602649},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CCDC47","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/YIPF6","total_profiled":1310},"omim":[{"mim_id":"617522","title":"YIP1 DOMAIN FAMILY, MEMBER 2; YIPF2","url":"https://www.omim.org/entry/617522"},{"mim_id":"617521","title":"YIP1 DOMAIN FAMILY, MEMBER 1; YIPF1","url":"https://www.omim.org/entry/617521"},{"mim_id":"300996","title":"YIP1 DOMAIN FAMILY, MEMBER 6; YIPF6","url":"https://www.omim.org/entry/300996"},{"mim_id":"300127","title":"OLIGOPHRENIN 1; OPHN1","url":"https://www.omim.org/entry/300127"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/YIPF6"},"hgnc":{"alias_symbol":["MGC21416","FinGER6","Yip4","YIPFalpha3"],"prev_symbol":[]},"alphafold":{"accession":"Q96EC8","domains":[{"cath_id":"-","chopping":"58-107_116-231","consensus_level":"high","plddt":84.6642,"start":58,"end":231}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96EC8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96EC8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96EC8-F1-predicted_aligned_error_v6.png","plddt_mean":73.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=YIPF6","jax_strain_url":"https://www.jax.org/strain/search?query=YIPF6"},"sequence":{"accession":"Q96EC8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96EC8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96EC8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96EC8"}},"corpus_meta":[{"pmid":"31608184","id":"PMC_31608184","title":"Identification of crucial genes in abdominal aortic aneurysm by WGCNA.","date":"2019","source":"PeerJ","url":"https://pubmed.ncbi.nlm.nih.gov/31608184","citation_count":88,"is_preprint":false},{"pmid":"30552321","id":"PMC_30552321","title":"TGNap1 is required for microtubule-dependent homeostasis of a subpopulation of the plant trans-Golgi network.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30552321","citation_count":40,"is_preprint":false},{"pmid":"31289229","id":"PMC_31289229","title":"YIPF6 controls sorting of FGF21 into COPII vesicles and promotes obesity.","date":"2019","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/31289229","citation_count":33,"is_preprint":false},{"pmid":"22802641","id":"PMC_22802641","title":"Yip1 domain family, member 6 (Yipf6) mutation induces spontaneous intestinal inflammation in mice.","date":"2012","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/22802641","citation_count":29,"is_preprint":false},{"pmid":"25914309","id":"PMC_25914309","title":"Novel candidate blood-based transcriptional biomarkers of Machado-Joseph disease.","date":"2015","source":"Movement disorders : official journal of the Movement Disorder Society","url":"https://pubmed.ncbi.nlm.nih.gov/25914309","citation_count":27,"is_preprint":false},{"pmid":"28144969","id":"PMC_28144969","title":"High levels of the AR-V7 Splice Variant and Co-Amplification of the Golgi Protein Coding YIPF6 in AR Amplified Prostate Cancer Bone Metastases.","date":"2017","source":"The Prostate","url":"https://pubmed.ncbi.nlm.nih.gov/28144969","citation_count":26,"is_preprint":false},{"pmid":"30913233","id":"PMC_30913233","title":"DNA methylation among firefighters.","date":"2019","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/30913233","citation_count":26,"is_preprint":false},{"pmid":"17178117","id":"PMC_17178117","title":"Tvp38, Tvp23, Tvp18 and Tvp15: novel membrane proteins in the Tlg2-containing Golgi/endosome compartments of Saccharomyces cerevisiae.","date":"2006","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/17178117","citation_count":26,"is_preprint":false},{"pmid":"21919029","id":"PMC_21919029","title":"Integrative genomic, transcriptomic, and RNAi analysis indicates a potential oncogenic role for FAM110B in castration-resistant prostate cancer.","date":"2011","source":"The Prostate","url":"https://pubmed.ncbi.nlm.nih.gov/21919029","citation_count":25,"is_preprint":false},{"pmid":"27999994","id":"PMC_27999994","title":"Functional characterisation of the YIPF protein family in mammalian cells.","date":"2016","source":"Histochemistry and cell 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\"method\": \"Forward genetic screen, electron microscopy, immunocytochemistry, gene expression analysis, DSS colitis model in Yipf6 null mice\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (EM, immunocytochemistry, in vivo genetics) in a well-controlled loss-of-function study, establishing specific cellular phenotype\",\n      \"pmids\": [\"22802641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"YIPF6 binds FGF21 in the endoplasmic reticulum and controls its packaging into COPII vesicles, thereby limiting FGF21 secretion; loss of YIPF6 function increases FGF21 plasma levels and confers resistance to diet-induced obesity in mice.\",\n      \"method\": \"Co-immunoprecipitation (YIPF6–FGF21 binding in ER), hepatocyte-specific FGF21 deletion epistasis, COPII vesicle sorting assay, plasma FGF21 measurement in Yipf6 mutant mice on high-fat diet\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding assay plus genetic epistasis (hepatocyte-specific FGF21 KO rescues obesity protection), multiple orthogonal methods in one study\",\n      \"pmids\": [\"31289229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"YIPF6 localizes to the Golgi apparatus and its overexpression in 22Rv1 prostate cancer cells reduces cell proliferation and colony formation while enhancing extracellular vesicle (EV) secretion; EVs from YIPF6-overexpressing cells are enriched for coagulation proteins and decrease activated partial thromboplastin time.\",\n      \"method\": \"Immunohistochemistry, confocal microscopy, siRNA knockdown and stable overexpression, cell proliferation/colony assays, EV isolation by size-exclusion chromatography, LC-MS/MS proteomics, APTT coagulation assay\",\n      \"journal\": \"The Prostate\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays in a single lab; Golgi localization confirmed by imaging; functional consequences of OE established but mechanistic pathway not fully resolved\",\n      \"pmids\": [\"28144969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"YIPF6 localizes broadly throughout the Golgi stack (both cis and trans compartments); its cytosol-facing N-terminal region and lumen-facing C-terminus define a five-transmembrane topology shared across YIPF family members; RNAi depletion of YIPF6 causes specific morphological changes to the Golgi.\",\n      \"method\": \"Fluorescence microscopy, membrane topology assays, RNAi knockdown with Golgi morphology readout in mammalian cells\",\n      \"journal\": \"Histochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with functional consequence (Golgi morphology), topology determined experimentally, single lab with two orthogonal methods\",\n      \"pmids\": [\"27999994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"YIPF6 forms stable complexes with YIPF1 and YIPF2 at the medial-/trans-Golgi and TGN; knockdown of YIPF6 reduces protein levels of YIPF1 and YIPF2, indicating YIPF6 is required for the stable expression and Golgi localization of its partners. Free YIPF6 (after dissociating from YIPF1/YIPF2) interferes with Golgi reassembly post-BFA treatment.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, BFA treatment/washout assay, siRNA knockdown with western blot and immunofluorescence readouts\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and functional knockdown with multiple readouts, single lab\",\n      \"pmids\": [\"28286305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TVP23B physically interacts with YIPF6 at the Golgi; both proteins are required for intestinal homeostasis and their deficiency results in a common loss of glycosylation enzymes from the Golgi proteome of colonocytes, linking YIPF6 to glycosylation enzyme trafficking.\",\n      \"method\": \"Forward genetic screen, co-immunoprecipitation (TVP23B–YIPF6 interaction), Golgi proteomics of TVP23B- and YIPF6-deficient colonocytes, in vivo colitis models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding interaction established by co-IP, proteomics provides mechanistic insight; single lab but orthogonal methods\",\n      \"pmids\": [\"37339972\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Yeast Yip4 (ortholog of YIPF6) resides in Tlg2-containing Golgi/endosome compartments and participates in a protein interaction network with Tvp23, Tvp18, and Tvp15; disruption of tvp15 or tvp23 shows synthetic aggravation with ypt6 or ric1 null mutations, placing Yip4 in the late Golgi/endosomal maintenance pathway.\",\n      \"method\": \"Immunofluorescence, immunoprecipitation of yeast Tvp proteins, genetic epistasis (double-mutant analysis), carboxypeptidase Y and alkaline phosphatase processing assays\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and genetic epistasis in yeast ortholog, single lab; pathway placement supported by multiple methods\",\n      \"pmids\": [\"17178117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Plant TGNap1 binds YIP4 (plant ortholog of YIPF6) and Rab6, and together these interactions contribute to microtubule-dependent biogenesis and function of a TGN subset, placing YIP4 in a Rab6/microtubule-dependent TGN trafficking pathway.\",\n      \"method\": \"Co-immunoprecipitation, live-cell imaging, genetic/RNAi loss-of-function in Arabidopsis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — findings are in plants (Arabidopsis), which is an ortholog but with potentially divergent function; single lab, binding shown but mechanistic role of YIP4 specifically not dissected in isolation\",\n      \"pmids\": [\"30552321\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"YIPF6 is a five-transmembrane Golgi-resident protein that forms stable complexes with YIPF1 and YIPF2 to support their expression and Golgi localization; it controls secretory granule biogenesis in intestinal Paneth and goblet cells, regulates FGF21 secretion by binding FGF21 in the ER and directing its packaging into COPII vesicles, interacts with the trans-Golgi protein TVP23B to maintain glycosylation enzyme trafficking, and modulates extracellular vesicle secretion, collectively placing YIPF6 as a key regulator of ER-to-Golgi cargo sorting and post-Golgi secretory pathway homeostasis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"YIPF6 is a five-transmembrane Golgi-resident protein that functions as a regulator of ER-to-Golgi cargo sorting and secretory pathway homeostasis, with a defining requirement in intestinal epithelial secretion [#0, #3]. Loss of YIPF6 in mice causes defective formation and secretion of large secretory granules from Paneth and goblet cells, producing spontaneous intestinal inflammation [#0]. The protein spans the Golgi stack across both cis and trans compartments, with a cytosol-facing N-terminus and a lumen-facing C-terminus, and its depletion alters Golgi morphology [#3]. YIPF6 assembles into a stable complex with YIPF1 and YIPF2 at the medial/trans-Golgi and TGN, and is required for the stable expression and Golgi localization of these partners [#4]. It also interacts with the trans-Golgi protein TVP23B, and loss of either protein depletes glycosylation enzymes from the colonocyte Golgi proteome, linking YIPF6 to glycosylation enzyme trafficking and intestinal homeostasis [#5]. In a distinct secretory role, YIPF6 binds FGF21 in the ER and controls its packaging into COPII vesicles, thereby limiting FGF21 secretion; its loss raises plasma FGF21 and confers resistance to diet-induced obesity [#1]. YIPF6 additionally modulates extracellular vesicle secretion in prostate cancer cells [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Establishing where the YIPF6 ortholog acts placed the protein in the late Golgi/endosomal maintenance machinery rather than the early secretory pathway.\",\n      \"evidence\": \"Immunoprecipitation and genetic epistasis of yeast Yip4 with Tvp and Ypt6/Ric1 components\",\n      \"pmids\": [\"17178117\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Yeast pathway placement may not transfer to mammalian YIPF6\", \"Direct cargo or molecular activity of Yip4 not defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"A forward-genetic loss-of-function model answered what YIPF6 does at the organismal level, revealing an essential role in secretory granule biogenesis in intestinal epithelium.\",\n      \"evidence\": \"Forward genetic screen, EM, immunocytochemistry and DSS colitis in Yipf6-null mice\",\n      \"pmids\": [\"22802641\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism linking YIPF6 to granule formation unresolved\", \"No biochemical partners identified in this study\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defining membrane topology and localization clarified how YIPF6 is positioned in the Golgi and that it is needed for Golgi structural integrity.\",\n      \"evidence\": \"Fluorescence microscopy, membrane topology assays and RNAi with Golgi morphology readout in mammalian cells\",\n      \"pmids\": [\"27999994\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Topology does not reveal catalytic or binding function\", \"Mechanism connecting depletion to morphology change unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identifying YIPF1/YIPF2 as stable partners showed YIPF6 acts within a Golgi YIP-family complex whose member stability it controls.\",\n      \"evidence\": \"Reciprocal co-IP, immunofluorescence, BFA washout and siRNA knockdown in mammalian cells\",\n      \"pmids\": [\"28286305\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Function of the YIPF1/2/6 complex in cargo sorting not defined\", \"Single-lab interaction data\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Overexpression studies in cancer cells linked YIPF6 to extracellular vesicle output and proliferation control, extending its role to post-Golgi secretion.\",\n      \"evidence\": \"siRNA/overexpression, EV isolation, LC-MS/MS proteomics and APTT assay in 22Rv1 prostate cancer cells\",\n      \"pmids\": [\"28144969\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Overexpression phenotype may not reflect endogenous function\", \"Mechanism connecting YIPF6 to EV biogenesis unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"A direct ER cargo-binding role was established, showing YIPF6 gates FGF21 entry into COPII vesicles and thereby controls a metabolic secretory output.\",\n      \"evidence\": \"Co-IP of ER YIPF6\\u2013FGF21 binding, COPII sorting assay, hepatocyte FGF21-KO epistasis and plasma FGF21 in Yipf6-mutant mice on high-fat diet\",\n      \"pmids\": [\"31289229\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether YIPF6 selects other COPII cargoes is unknown\", \"Structural basis of FGF21 recognition not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The TVP23B interaction tied YIPF6 mechanistically to maintenance of Golgi glycosylation enzymes, explaining part of its intestinal homeostasis function.\",\n      \"evidence\": \"Forward genetic screen, co-IP and Golgi proteomics of TVP23B- and YIPF6-deficient colonocytes with in vivo colitis models\",\n      \"pmids\": [\"37339972\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How the YIPF6\\u2013TVP23B complex retains glycosyltransferases is unclear\", \"Direct enzyme cargo not identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The unifying molecular activity of YIPF6 \\u2014 how a single Golgi YIP-family protein coordinates COPII cargo selection, complex-member stabilization, and glycosylation-enzyme retention \\u2014 remains undefined.\",\n      \"evidence\": \"No reconstituted biochemical or structural study of YIPF6 in the corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structure of YIPF6 or its complexes\", \"No defined biochemical activity beyond cargo/partner binding\", \"Relationship between ER FGF21 binding and Golgi complex roles not integrated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [0, 2, 3, 4, 5]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [1, 5]}\n    ],\n    \"complexes\": [\"YIPF1-YIPF2-YIPF6 Golgi complex\"],\n    \"partners\": [\"YIPF1\", \"YIPF2\", \"FGF21\", \"TVP23B\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}