{"gene":"YIPF6","run_date":"2026-04-28T23:00:23","timeline":{"discoveries":[{"year":2012,"finding":"YIPF6 (Yipf6) is a five transmembrane-spanning protein associated with Golgi compartments; null mutation in mice causes defective formation and secretion of large secretory granules from Paneth and goblet cells, leading to spontaneous intestinal inflammation and hypersensitivity to DSS-induced colitis.","method":"Forward genetic screen, electron microscopy, immunocytochemistry, gene expression analysis in Yipf6 null (Klein-Zschocher) mice","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined cellular phenotype (secretory granule defect) plus multiple orthogonal methods, replicated in follow-up studies","pmids":["22802641"],"is_preprint":false},{"year":2016,"finding":"YIPF6 localizes throughout the Golgi stack (broader than other family members), has a cytosol-facing N-terminal region and 5 closely stacked transmembrane domains with a lumen-facing C-terminus; RNAi-mediated depletion causes specific morphological changes to the Golgi complex.","method":"Immunofluorescence microscopy, membrane topology assays, RNA interference with Golgi morphology readout","journal":"Histochemistry and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization and topology experiment with functional (morphological) consequence, single study","pmids":["27999994"],"is_preprint":false},{"year":2017,"finding":"YIPF6 forms stable complexes separately with YIPF1 and YIPF2 in the medial-/trans-Golgi; knockdown of YIPF6 reduces YIPF1 and YIPF2 protein levels, indicating YIPF6 is required for their stable expression and Golgi localization. Free YIPF6 (after dissociation from YIPF1/YIPF2) interferes with Golgi reassembly after brefeldin A washout.","method":"Co-immunoprecipitation, immunofluorescence, siRNA knockdown, brefeldin A washout assay","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal co-IP plus functional knockdown with defined phenotype, single laboratory","pmids":["28286305"],"is_preprint":false},{"year":2019,"finding":"YIPF6 binds FGF21 in the endoplasmic reticulum to limit its secretion and specifies the packaging of FGF21 into COPII vesicles; loss-of-function (Yipf6 mutation) increases plasma FGF21 levels and hepatocyte FGF21 secretion, protecting mice from high-fat diet-induced metabolic syndrome in an FGF21-dependent manner.","method":"Co-immunoprecipitation (YIPF6–FGF21 binding in ER), hepatocyte secretion assay, hepatocyte-specific FGF21 deletion epistasis, mouse metabolic phenotyping","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — direct binding assay plus genetic epistasis (FGF21 liver KO rescues phenotype) plus multiple metabolic readouts, strong mechanistic evidence","pmids":["31289229"],"is_preprint":false},{"year":2023,"finding":"YIPF6 physically interacts with TVP23B (a trans-Golgi membrane protein); both are required for intestinal homeostasis, and their deficiency leads to a common loss of critical glycosylation enzymes from the Golgi proteome of colonocytes, impairing mucin glycosylation and Paneth cell antimicrobial peptide secretion.","method":"Forward genetic screen, co-immunoprecipitation (TVP23B–YIPF6 interaction), Golgi proteomics of YIPF6- and TVP23B-deficient colonocytes, in vivo intestinal homeostasis assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — direct protein interaction demonstrated, orthogonal proteomics, and clear functional phenotype; complements earlier Yipf6 KO data","pmids":["37339972"],"is_preprint":false},{"year":2017,"finding":"YIPF6 protein localizes to the Golgi apparatus in prostate cancer cells; overexpression of YIPF6 in 22Rv1 cells reduces cell proliferation and colony formation and enhances extracellular vesicle (EV) secretion enriched for pro-coagulative proteins.","method":"Immunohistochemistry, confocal microscopy, siRNA knockdown and stable overexpression, cell proliferation/colony formation assays, nanoparticle tracking analysis, LC-MS/MS proteomics of EVs, APTT coagulation assay","journal":"The Prostate","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal functional assays in a single study; mechanistic link between YIPF6 and EV secretion pathway established","pmids":["28144969"],"is_preprint":false},{"year":2006,"finding":"The yeast orthologs Tvp23 and Tvp18 (homologs of mammalian TVP23B-interacting partners) co-immunoprecipitate with Yip1-family proteins Yip4 and Yip5 (orthologs of YIPF6-related proteins) in the Tlg2-containing late Golgi/endosomal compartments; disruption of tvp15 and tvp23 shows synthetic aggravation with ypt6 or ric1 null mutations, placing these proteins in the Ypt6/Rab6 pathway.","method":"Immunoprecipitation, immunofluorescence, genetic epistasis (synthetic lethality screen), carboxypeptidase Y and alkaline phosphatase processing assays","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP plus genetic epistasis in yeast; ortholog context consistent with mammalian YIPF6 function","pmids":["17178117"],"is_preprint":false}],"current_model":"YIPF6 is a multi-transmembrane Golgi protein that forms complexes with YIPF1/YIPF2 and TVP23B to maintain Golgi glycosylation enzyme composition and membrane homeostasis; it binds FGF21 in the ER to restrict its loading into COPII vesicles and limit secretion, and is required for the biogenesis of large secretory granules in intestinal Paneth and goblet cells, with loss of function causing defective glycosylation, impaired antimicrobial secretion, and spontaneous intestinal inflammation."},"narrative":{"teleology":[{"year":2006,"claim":"Establishing the ancestral pathway context: yeast homologs of YIPF6-family proteins were shown to physically associate with TVP23-family proteins at the late Golgi and to function genetically in the Ypt6/Rab6 pathway, placing the Yip1/TVP23 module in Golgi-to-endosome trafficking.","evidence":"Co-IP plus synthetic-lethal genetic epistasis with ypt6/ric1 in yeast","pmids":["17178117"],"confidence":"Medium","gaps":["Mammalian YIPF6–TVP23B interaction not yet demonstrated at this time","Precise cargo or membrane trafficking step controlled by the module was undefined"]},{"year":2012,"claim":"A forward genetic screen revealed that YIPF6 is essential for the biogenesis and secretion of large secretory granules in intestinal Paneth and goblet cells, linking it to mucosal defense and demonstrating that its loss causes spontaneous intestinal inflammation.","evidence":"ENU-derived Yipf6-null mice analyzed by electron microscopy, immunocytochemistry, DSS colitis challenge","pmids":["22802641"],"confidence":"High","gaps":["Whether the granule defect reflects a Golgi sorting, maturation, or trafficking failure was unresolved","Direct protein partners of YIPF6 were unknown"]},{"year":2016,"claim":"Determination of YIPF6 membrane topology and pan-Golgi distribution clarified that it spans the Golgi membrane five times with a cytosolic N-terminus and lumenal C-terminus, and that its depletion alters Golgi morphology.","evidence":"Protease-accessibility topology assay, immunofluorescence, siRNA knockdown in cultured cells","pmids":["27999994"],"confidence":"Medium","gaps":["Single-study topology determination; no structural data","Which Golgi functions depend on YIPF6 remained unclear"]},{"year":2017,"claim":"Identification of YIPF1 and YIPF2 as stable Golgi-resident binding partners of YIPF6 showed that YIPF6 is required for their stability and Golgi retention, and that free YIPF6 can dominantly interfere with post-BFA Golgi reassembly, establishing YIPF6 as a scaffold within YIPF-family complexes.","evidence":"Reciprocal co-IP, siRNA knockdown with protein-level readout, BFA washout Golgi reassembly assay","pmids":["28286305"],"confidence":"Medium","gaps":["Stoichiometry and structural basis of the YIPF6–YIPF1/YIPF2 complexes unknown","How these complexes relate to secretory granule formation was not addressed"]},{"year":2017,"claim":"Overexpression studies in prostate cancer cells demonstrated that YIPF6 can suppress proliferation and enhance extracellular vesicle secretion, extending its role beyond conventional secretory granules to broader vesicular trafficking.","evidence":"Stable overexpression and siRNA in 22Rv1 cells; proliferation, colony formation, NTA, and EV proteomics","pmids":["28144969"],"confidence":"Medium","gaps":["Single cancer cell line; generalizability to other cell types uncertain","Mechanism connecting YIPF6 to EV biogenesis versus conventional secretion not delineated"]},{"year":2019,"claim":"YIPF6 was found to act as a cargo-selective gatekeeper in the ER, binding FGF21 and restricting its loading into COPII vesicles; genetic epistasis proved that the metabolic protection observed in Yipf6-mutant mice depends entirely on elevated FGF21 secretion.","evidence":"Co-IP of YIPF6–FGF21 in ER fraction, hepatocyte secretion assay, liver-specific FGF21 knockout epistasis, high-fat diet metabolic phenotyping","pmids":["31289229"],"confidence":"High","gaps":["Whether YIPF6 acts as a direct retention receptor or an indirect sorting factor for FGF21 is unresolved","Other ER-to-Golgi cargo regulated by YIPF6 not identified"]},{"year":2023,"claim":"Physical interaction between YIPF6 and TVP23B was demonstrated, and Golgi proteomics of their respective knockout colonocytes converged on a shared loss of glycosylation enzymes, unifying the secretory granule and glycosylation defects into a common Golgi quality-control mechanism for intestinal homeostasis.","evidence":"Co-IP of YIPF6–TVP23B, Golgi proteomics from YIPF6- and TVP23B-deficient mouse colonocytes, intestinal phenotyping","pmids":["37339972"],"confidence":"High","gaps":["How the YIPF6–TVP23B complex retains glycosylation enzymes in the Golgi is mechanistically undefined","Relationship between the YIPF6–YIPF1/2 and YIPF6–TVP23B complexes (overlapping or distinct) is unknown"]},{"year":null,"claim":"The structural basis for YIPF6 complex assembly, how it discriminates between ER and Golgi cargo, and whether it functions as a direct retention receptor versus a trafficking adaptor remain open questions.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of YIPF6 or any of its complexes","Full repertoire of ER-exit and Golgi-resident cargo regulated by YIPF6 is unknown","Mechanism by which the YIPF6–TVP23B complex maintains Golgi glycosylation enzyme composition is undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,3,4]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[0,1,2,4,5]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,3,5]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[3,4]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[4]}],"complexes":["YIPF6–YIPF1 complex","YIPF6–YIPF2 complex","YIPF6–TVP23B complex"],"partners":["YIPF1","YIPF2","TVP23B","FGF21"],"other_free_text":[]},"mechanistic_narrative":"YIPF6 is a five-transmembrane Golgi protein that controls secretory granule biogenesis, cargo sorting in the early secretory pathway, and Golgi membrane homeostasis. It forms stable complexes with YIPF1 and YIPF2 in the medial-/trans-Golgi and is required for their protein stability, while also interacting with TVP23B to maintain the Golgi glycosylation enzyme complement needed for proper mucin glycosylation and Paneth cell antimicrobial peptide secretion [PMID:28286305, PMID:37339972]. In the endoplasmic reticulum, YIPF6 binds FGF21 to restrict its loading into COPII vesicles, thereby limiting FGF21 secretion; loss of YIPF6 elevates circulating FGF21 and protects mice from diet-induced metabolic syndrome in an FGF21-dependent manner [PMID:31289229]. Yipf6-null mice exhibit defective large secretory granule formation in intestinal Paneth and goblet cells, leading to impaired antimicrobial secretion and spontaneous intestinal inflammation [PMID:22802641]."},"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":"23832588","id":"PMC_23832588","title":"Trans-Golgi network localized ECHIDNA/Ypt interacting protein complex is required for the secretion of cell wall polysaccharides in Arabidopsis.","date":"2013","source":"The Plant cell","url":"https://pubmed.ncbi.nlm.nih.gov/23832588","citation_count":111,"is_preprint":false},{"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":"28917589","id":"PMC_28917589","title":"A Novel RGL2-DOF6 Complex Contributes to Primary Seed Dormancy in Arabidopsis thaliana by Regulating a GATA Transcription Factor.","date":"2017","source":"Molecular plant","url":"https://pubmed.ncbi.nlm.nih.gov/28917589","citation_count":81,"is_preprint":false},{"pmid":"30552321","id":"PMC_30552321","title":"TGNap1 is required for microtubule-dependent homeostasis of a subpopulation of the plant trans-Golgi 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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":"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":"30913233","id":"PMC_30913233","title":"DNA methylation among firefighters.","date":"2019","source":"PloS 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in mice causes defective formation and secretion of large secretory granules from Paneth and goblet cells, leading to spontaneous intestinal inflammation and hypersensitivity to DSS-induced colitis.\",\n      \"method\": \"Forward genetic screen, electron microscopy, immunocytochemistry, gene expression analysis in Yipf6 null (Klein-Zschocher) mice\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotype (secretory granule defect) plus multiple orthogonal methods, replicated in follow-up studies\",\n      \"pmids\": [\"22802641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"YIPF6 localizes throughout the Golgi stack (broader than other family members), has a cytosol-facing N-terminal region and 5 closely stacked transmembrane domains with a lumen-facing C-terminus; RNAi-mediated depletion causes specific morphological changes to the Golgi complex.\",\n      \"method\": \"Immunofluorescence microscopy, membrane topology assays, RNA interference with Golgi morphology readout\",\n      \"journal\": \"Histochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization and topology experiment with functional (morphological) consequence, single study\",\n      \"pmids\": [\"27999994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"YIPF6 forms stable complexes separately with YIPF1 and YIPF2 in the medial-/trans-Golgi; knockdown of YIPF6 reduces YIPF1 and YIPF2 protein levels, indicating YIPF6 is required for their stable expression and Golgi localization. Free YIPF6 (after dissociation from YIPF1/YIPF2) interferes with Golgi reassembly after brefeldin A washout.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, siRNA knockdown, brefeldin A washout assay\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP plus functional knockdown with defined phenotype, single laboratory\",\n      \"pmids\": [\"28286305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"YIPF6 binds FGF21 in the endoplasmic reticulum to limit its secretion and specifies the packaging of FGF21 into COPII vesicles; loss-of-function (Yipf6 mutation) increases plasma FGF21 levels and hepatocyte FGF21 secretion, protecting mice from high-fat diet-induced metabolic syndrome in an FGF21-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation (YIPF6–FGF21 binding in ER), hepatocyte secretion assay, hepatocyte-specific FGF21 deletion epistasis, mouse metabolic phenotyping\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct binding assay plus genetic epistasis (FGF21 liver KO rescues phenotype) plus multiple metabolic readouts, strong mechanistic evidence\",\n      \"pmids\": [\"31289229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YIPF6 physically interacts with TVP23B (a trans-Golgi membrane protein); both are required for intestinal homeostasis, and their deficiency leads to a common loss of critical glycosylation enzymes from the Golgi proteome of colonocytes, impairing mucin glycosylation and Paneth cell antimicrobial peptide secretion.\",\n      \"method\": \"Forward genetic screen, co-immunoprecipitation (TVP23B–YIPF6 interaction), Golgi proteomics of YIPF6- and TVP23B-deficient colonocytes, in vivo intestinal homeostasis assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct protein interaction demonstrated, orthogonal proteomics, and clear functional phenotype; complements earlier Yipf6 KO data\",\n      \"pmids\": [\"37339972\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"YIPF6 protein localizes to the Golgi apparatus in prostate cancer cells; overexpression of YIPF6 in 22Rv1 cells reduces cell proliferation and colony formation and enhances extracellular vesicle (EV) secretion enriched for pro-coagulative proteins.\",\n      \"method\": \"Immunohistochemistry, confocal microscopy, siRNA knockdown and stable overexpression, cell proliferation/colony formation assays, nanoparticle tracking analysis, LC-MS/MS proteomics of EVs, APTT coagulation assay\",\n      \"journal\": \"The Prostate\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal functional assays in a single study; mechanistic link between YIPF6 and EV secretion pathway established\",\n      \"pmids\": [\"28144969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The yeast orthologs Tvp23 and Tvp18 (homologs of mammalian TVP23B-interacting partners) co-immunoprecipitate with Yip1-family proteins Yip4 and Yip5 (orthologs of YIPF6-related proteins) in the Tlg2-containing late Golgi/endosomal compartments; disruption of tvp15 and tvp23 shows synthetic aggravation with ypt6 or ric1 null mutations, placing these proteins in the Ypt6/Rab6 pathway.\",\n      \"method\": \"Immunoprecipitation, immunofluorescence, genetic epistasis (synthetic lethality screen), carboxypeptidase Y and alkaline phosphatase processing assays\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP plus genetic epistasis in yeast; ortholog context consistent with mammalian YIPF6 function\",\n      \"pmids\": [\"17178117\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"YIPF6 is a multi-transmembrane Golgi protein that forms complexes with YIPF1/YIPF2 and TVP23B to maintain Golgi glycosylation enzyme composition and membrane homeostasis; it binds FGF21 in the ER to restrict its loading into COPII vesicles and limit secretion, and is required for the biogenesis of large secretory granules in intestinal Paneth and goblet cells, with loss of function causing defective glycosylation, impaired antimicrobial secretion, and spontaneous intestinal inflammation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"YIPF6 is a five-transmembrane Golgi protein that controls secretory granule biogenesis, cargo sorting in the early secretory pathway, and Golgi membrane homeostasis. It forms stable complexes with YIPF1 and YIPF2 in the medial-/trans-Golgi and is required for their protein stability, while also interacting with TVP23B to maintain the Golgi glycosylation enzyme complement needed for proper mucin glycosylation and Paneth cell antimicrobial peptide secretion [PMID:28286305, PMID:37339972]. In the endoplasmic reticulum, YIPF6 binds FGF21 to restrict its loading into COPII vesicles, thereby limiting FGF21 secretion; loss of YIPF6 elevates circulating FGF21 and protects mice from diet-induced metabolic syndrome in an FGF21-dependent manner [PMID:31289229]. Yipf6-null mice exhibit defective large secretory granule formation in intestinal Paneth and goblet cells, leading to impaired antimicrobial secretion and spontaneous intestinal inflammation [PMID:22802641].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Establishing the ancestral pathway context: yeast homologs of YIPF6-family proteins were shown to physically associate with TVP23-family proteins at the late Golgi and to function genetically in the Ypt6/Rab6 pathway, placing the Yip1/TVP23 module in Golgi-to-endosome trafficking.\",\n      \"evidence\": \"Co-IP plus synthetic-lethal genetic epistasis with ypt6/ric1 in yeast\",\n      \"pmids\": [\"17178117\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mammalian YIPF6–TVP23B interaction not yet demonstrated at this time\",\n        \"Precise cargo or membrane trafficking step controlled by the module was undefined\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"A forward genetic screen revealed that YIPF6 is essential for the biogenesis and secretion of large secretory granules in intestinal Paneth and goblet cells, linking it to mucosal defense and demonstrating that its loss causes spontaneous intestinal inflammation.\",\n      \"evidence\": \"ENU-derived Yipf6-null mice analyzed by electron microscopy, immunocytochemistry, DSS colitis challenge\",\n      \"pmids\": [\"22802641\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the granule defect reflects a Golgi sorting, maturation, or trafficking failure was unresolved\",\n        \"Direct protein partners of YIPF6 were unknown\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Determination of YIPF6 membrane topology and pan-Golgi distribution clarified that it spans the Golgi membrane five times with a cytosolic N-terminus and lumenal C-terminus, and that its depletion alters Golgi morphology.\",\n      \"evidence\": \"Protease-accessibility topology assay, immunofluorescence, siRNA knockdown in cultured cells\",\n      \"pmids\": [\"27999994\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-study topology determination; no structural data\",\n        \"Which Golgi functions depend on YIPF6 remained unclear\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identification of YIPF1 and YIPF2 as stable Golgi-resident binding partners of YIPF6 showed that YIPF6 is required for their stability and Golgi retention, and that free YIPF6 can dominantly interfere with post-BFA Golgi reassembly, establishing YIPF6 as a scaffold within YIPF-family complexes.\",\n      \"evidence\": \"Reciprocal co-IP, siRNA knockdown with protein-level readout, BFA washout Golgi reassembly assay\",\n      \"pmids\": [\"28286305\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Stoichiometry and structural basis of the YIPF6–YIPF1/YIPF2 complexes unknown\",\n        \"How these complexes relate to secretory granule formation was not addressed\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Overexpression studies in prostate cancer cells demonstrated that YIPF6 can suppress proliferation and enhance extracellular vesicle secretion, extending its role beyond conventional secretory granules to broader vesicular trafficking.\",\n      \"evidence\": \"Stable overexpression and siRNA in 22Rv1 cells; proliferation, colony formation, NTA, and EV proteomics\",\n      \"pmids\": [\"28144969\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single cancer cell line; generalizability to other cell types uncertain\",\n        \"Mechanism connecting YIPF6 to EV biogenesis versus conventional secretion not delineated\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"YIPF6 was found to act as a cargo-selective gatekeeper in the ER, binding FGF21 and restricting its loading into COPII vesicles; genetic epistasis proved that the metabolic protection observed in Yipf6-mutant mice depends entirely on elevated FGF21 secretion.\",\n      \"evidence\": \"Co-IP of YIPF6–FGF21 in ER fraction, hepatocyte secretion assay, liver-specific FGF21 knockout epistasis, high-fat diet metabolic phenotyping\",\n      \"pmids\": [\"31289229\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether YIPF6 acts as a direct retention receptor or an indirect sorting factor for FGF21 is unresolved\",\n        \"Other ER-to-Golgi cargo regulated by YIPF6 not identified\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Physical interaction between YIPF6 and TVP23B was demonstrated, and Golgi proteomics of their respective knockout colonocytes converged on a shared loss of glycosylation enzymes, unifying the secretory granule and glycosylation defects into a common Golgi quality-control mechanism for intestinal homeostasis.\",\n      \"evidence\": \"Co-IP of YIPF6–TVP23B, Golgi proteomics from YIPF6- and TVP23B-deficient mouse colonocytes, intestinal phenotyping\",\n      \"pmids\": [\"37339972\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How the YIPF6–TVP23B complex retains glycosylation enzymes in the Golgi is mechanistically undefined\",\n        \"Relationship between the YIPF6–YIPF1/2 and YIPF6–TVP23B complexes (overlapping or distinct) is unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis for YIPF6 complex assembly, how it discriminates between ER and Golgi cargo, and whether it functions as a direct retention receptor versus a trafficking adaptor remain open questions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No high-resolution structure of YIPF6 or any of its complexes\",\n        \"Full repertoire of ER-exit and Golgi-resident cargo regulated by YIPF6 is unknown\",\n        \"Mechanism by which the YIPF6–TVP23B complex maintains Golgi glycosylation enzyme composition is undefined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 3, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [0, 1, 2, 4, 5]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 3, 5]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [\n      \"YIPF6–YIPF1 complex\",\n      \"YIPF6–YIPF2 complex\",\n      \"YIPF6–TVP23B complex\"\n    ],\n    \"partners\": [\n      \"YIPF1\",\n      \"YIPF2\",\n      \"TVP23B\",\n      \"FGF21\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}