{"gene":"YIF1A","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2000,"finding":"Yif1p (yeast ortholog of YIF1A) forms a tight complex with Yip1p on Golgi membranes; the hydrophilic N-terminal half of Yif1p faces the cytosol and can interact with transport GTPases Ypt1p, Ypt31p, and Sec4p in two-hybrid analyses. Loss of Yif1p function in conditional-lethal mutants causes a block of ER-to-Golgi protein transport and accumulation of ER membranes and 40–50 nm vesicles. Genetic analyses suggest Yif1p acts downstream of Yip1p.","method":"Yeast two-hybrid, protein affinity studies, conditional-lethal mutant analysis, electron microscopy","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (two-hybrid, genetic epistasis, morphological phenotype) in a focused study of the yeast ortholog","pmids":["10970842"],"is_preprint":false},{"year":2001,"finding":"Yif1p (yeast ortholog) is selectively and efficiently packaged into COPII vesicles, establishing its presence in ER-derived transport vesicles.","method":"Purification of COPII vesicles followed by MALDI mass spectrometry and antibody-based localization","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mass spectrometry identification on purified vesicles plus antibody verification, single study","pmids":["11157978"],"is_preprint":false},{"year":2002,"finding":"Yif1p is a Yip1p-related protein that biochemically interacts with a variety of Rab/Ypt GTPases in a manner dependent on C-terminal prenylation of the GTPases, and physically associates with other YIP1 family members.","method":"In vitro biochemical binding assays, sequence analysis","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding assays with prenylation-dependence test, single lab","pmids":["11943201"],"is_preprint":false},{"year":2003,"finding":"The Yip1p–Yif1p complex is required for fusion competence of ER-derived vesicles with the Golgi in vitro. Anti-Yif1p antibodies added before vesicle budding block membrane fusion without affecting packaging of Yif1p, Yip1p, or SNAREs into vesicles. The Yip1p–Yif1p complex binds ER-to-Golgi SNAREs Bos1p and Sec22p.","method":"In vitro ER-to-Golgi transport assay with antibody inhibition; co-immunoprecipitation of SNARE binding partners","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted cell-free fusion assay plus co-IP of SNARE partners, rigorous epistatic placement of antibody addition timing","pmids":["12657649"],"is_preprint":false},{"year":2003,"finding":"Btn2p interacts with Yif1p (yeast ortholog) and is required for its correct localization; deletion of BTN2 results in mislocalization of Yif1p to the vacuole, demonstrating Btn2p-dependent retrieval of Yif1p to the Golgi.","method":"Yeast two-hybrid, genetic deletion, fluorescence localization","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two-hybrid plus deletion phenotype with localization readout, single lab","pmids":["12615067"],"is_preprint":false},{"year":2003,"finding":"Human YIF1A (HsYif1) belongs to a five-pass transmembrane protein family (FinGERs) that localizes to the Golgi apparatus and ER; overexpression of certain family members causes Golgi fragmentation, and family members interact with each other in yeast two-hybrid analyses.","method":"Immunofluorescence localization, yeast two-hybrid, overexpression phenotype","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — localization confirmed by immunofluorescence, overexpression phenotype observed, two-hybrid interactions; multiple orthogonal observations but limited functional mechanistic depth","pmids":["14680843"],"is_preprint":false},{"year":2004,"finding":"The N-terminal cytoplasmic domain of Yif1p mediates interactions with PX domain-containing proteins (Grd19p, Vam7p, Vps17p, Ypt35p) as determined by two-hybrid and in vitro binding assays. A lipid-binding mutation in Ypt35p does not affect its protein interaction with Yif1p, indicating the protein-binding surface is distinct from the lipid-binding pocket.","method":"Yeast two-hybrid genome-wide screen; in vitro binding assays","journal":"Molecular & cellular proteomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two-hybrid plus in vitro binding with domain dissection, single study","pmids":["15263065"],"is_preprint":false},{"year":2005,"finding":"Yos1p is a novel subunit of the Yip1p–Yif1p complex; it localizes to ER and Golgi membranes, is packaged into COPII vesicles, and associates with both Yip1p and Yif1p. Yos1p is essential and its depletion blocks ER-to-Golgi transport.","method":"Co-immunoprecipitation, subcellular fractionation, COPII vesicle packaging assay, genetic depletion","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP, vesicle packaging assay, and loss-of-function phenotype in multiple orthogonal experiments","pmids":["15659647"],"is_preprint":false},{"year":2005,"finding":"Human YIF1A (HsYif1) co-distributes with the Golgi marker GS27; it interacts with human Yip1A (HsYip1A) by yeast two-hybrid and immunoprecipitation; overexpression of a cytosolic-region-deleted mutant of HsYip1A disrupts YIF1A localization to the Golgi, showing that HsYip1A specifies YIF1A Golgi localization.","method":"Immunofluorescence, yeast two-hybrid, co-immunoprecipitation, dominant-negative overexpression","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction confirmed by two methods (two-hybrid + co-IP) and localization disruption by dominant-negative; single lab","pmids":["15990086"],"is_preprint":false},{"year":2006,"finding":"Btn2p (a Hook1 ortholog) facilitates retrieval of Yif1p from late endosomes back to the Golgi; deletion of BTN2 blocks Yif1p retrieval and results in Yif1p delivery to the vacuole. Similar mislocalization occurs in ypt6Δ, snx4Δ, and vps26Δ strains.","method":"Immunoprecipitation, in vitro GST-binding assay, fluorescence microscopy with GFP-tagged proteins, genetic deletion analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP, in vitro binding, fluorescence localization, and genetic epistasis across multiple deletion backgrounds","pmids":["17101785"],"is_preprint":false},{"year":2008,"finding":"Yif1B (a mammalian paralog closely related to YIF1A) interacts with the C-terminal domain of the 5-HT1A serotonin receptor and is required for targeting of 5-HT1A to distal dendrites; siRNA knockdown of Yif1B prevents dendritic addressing of 5-HT1A without affecting other receptors (sst2A, P2X2, 5-HT3A). Yif1B colocalizes with 5-HT1A in small trafficking vesicles.","method":"Yeast two-hybrid, GST pull-down from brain extracts and transfected cells, siRNA knockdown, immunofluorescence colocalization","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — note this is Yif1B (paralog), not YIF1A itself; included because it is the closest mammalian paralog and HGNC aliases include YIF1; multiple orthogonal methods, single lab","pmids":["18685031"],"is_preprint":false},{"year":2013,"finding":"YIF1A interacts with VAPB via transmembrane regions; YIF1A localizes to ER-Golgi intermediate compartments (ERGICs) in rat hippocampal neurons, recycles between ER and Golgi. VAPB is required for membrane trafficking into dendrites and normal dendritic morphology. The ALS8-linked VAPB-P56S mutant recruits YIF1A to its ER-like clusters, displacing YIF1A from its ERGIC localization.","method":"Co-immunoprecipitation, immunofluorescence localization in neurons, live imaging, siRNA knockdown, dominant-negative overexpression","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, neuronal localization, loss-of-function trafficking phenotype, and pathological mutant displacement, multiple orthogonal methods in one study","pmids":["23736259"],"is_preprint":false},{"year":2013,"finding":"YIF1A knockdown does not cause ER whorl formation (a phenotype caused by Yip1A depletion), demonstrating that Yip1A's ability to regulate ER structure can be uncoupled from its interaction with YIF1A.","method":"siRNA knockdown, fluorescence microscopy for ER morphology","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean knockdown with defined morphological readout, single lab, result is a negative finding informative for pathway dissection","pmids":["23342155"],"is_preprint":false},{"year":2014,"finding":"YIF1A was identified as an interactor of tumor protein TPD52 and TPD52L1 in a low-stringency yeast two-hybrid screen.","method":"Yeast two-hybrid screen","journal":"Molecular biology reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single two-hybrid identification, not validated by orthogonal method for YIF1A specifically","pmids":["24604726"],"is_preprint":false},{"year":2015,"finding":"GFP-tagged Yif1 (yeast) serves as a model Golgi quality-control substrate that is targeted to the vacuole upon amino acid starvation and TOR inactivation in a process dependent on ubiquitination by the DSC complex (including Tul1 E3 ligase) and upregulation of the VPS/ESCRT pathway via proteasome-mediated degradation of ESCRT-0.","method":"Fluorescence microscopy, genetic screens, deletion analysis, epistasis experiments","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with multiple deletions and pharmacological treatments, single lab","pmids":["26344761"],"is_preprint":false},{"year":2017,"finding":"YIPF1 and YIPF2 (mammalian Yif1p homologs, distinct from YIF1A) localize to medial-/trans-Golgi; YIPF6 forms stable complexes separately with YIPF1 and YIPF2 and is required for their stable expression. Knockdown of YIPF1 and YIPF2 delays Golgi reassembly after BFA washout and reduces intracellular glycan levels.","method":"Immunofluorescence, co-immunoprecipitation, siRNA knockdown, brefeldin A reassembly assay, glycan analysis","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — note these are YIPF1/YIPF2 paralogs not YIF1A; included for context of the YIF1A family; multiple orthogonal methods, single lab","pmids":["28286305"],"is_preprint":false},{"year":2018,"finding":"Drosophila Yif1 forms a protein complex with Yip1 in S2 cells and ddaC neurons, colocalizes with Yip1 on ER/Golgi, and is required for integrity of the Golgi apparatus and Golgi outposts. Loss of Yif1 blocks dendrite pruning of ddaC sensory neurons during metamorphosis by impairing ER-to-Golgi transport, which in turn prevents endocytosis and downregulation of the cell-adhesion molecule Neuroglian.","method":"Clonal genetic screen, co-immunoprecipitation in S2 cells, immunofluorescence, live imaging, genetic epistasis with Rab1 and Sar1","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP, in vivo loss-of-function with defined cellular phenotype, genetic epistasis with known ER-Golgi regulators, Drosophila ortholog study","pmids":["29769219"],"is_preprint":false}],"current_model":"YIF1A is an integral multi-pass transmembrane protein that localizes primarily to the ER-Golgi intermediate compartment (ERGIC) and Golgi apparatus, where it forms a stable complex with Yip1A (via transmembrane regions) and participates in COPII vesicle-mediated ER-to-Golgi transport by establishing fusion competence of ER-derived vesicles through interaction with ER-Golgi SNAREs; in neurons, YIF1A is required for membrane trafficking into dendrites, and its ERGIC localization is disrupted by the ALS8-linked VAPB-P56S mutation, which sequesters YIF1A into ER-like inclusions."},"narrative":{"mechanistic_narrative":"YIF1A is an integral multi-pass transmembrane protein of the ER–Golgi system that functions in COPII-dependent ER-to-Golgi membrane transport, characterized largely through its yeast ortholog Yif1p [PMID:10970842, PMID:12657649]. Yif1p forms a tight, stable complex with the YIP1-family protein Yip1p, acting downstream of Yip1p; loss of Yif1p function blocks ER-to-Golgi protein transport and causes accumulation of ER membranes and 40–50 nm vesicles [PMID:10970842]. This complex, together with the additional subunit Yos1p, is efficiently packaged into COPII vesicles and is required for the fusion competence of ER-derived vesicles with the Golgi, an activity it confers in part through binding the ER-to-Golgi SNAREs Bos1p and Sec22p [PMID:11157978, PMID:12657649, PMID:15659647]. The cytosolic N-terminal domain interacts with transport Rab/Ypt GTPases in a prenylation-dependent manner, coupling the complex to vesicle-trafficking GTPases [PMID:10970842, PMID:11943201]. The human protein localizes to the Golgi and ER and belongs to a five-pass transmembrane (FinGER/YIPF) family whose members interact with one another and whose overexpression fragments the Golgi [PMID:14680843]; human YIF1A binds human Yip1A, which specifies its Golgi localization [PMID:15990086]. In neurons, YIF1A localizes to the ER–Golgi intermediate compartment, recycles between ER and Golgi, and interacts via its transmembrane regions with VAPB to support membrane trafficking into dendrites; the ALS8-linked VAPB-P56S mutant sequesters YIF1A into ER-like inclusions, displacing it from the ERGIC [PMID:23736259]. YIF1A function is separable from Yip1A's role in regulating ER structure, since YIF1A knockdown does not reproduce the ER whorl phenotype of Yip1A depletion [PMID:23342155].","teleology":[{"year":2000,"claim":"Established that Yif1p partners with Yip1p and is functionally required for ER-to-Golgi transport, defining the gene's core trafficking role and its epistatic position downstream of Yip1p.","evidence":"Yeast two-hybrid, affinity studies, conditional-lethal mutants, and electron microscopy of the yeast ortholog","pmids":["10970842"],"confidence":"High","gaps":["Mechanism by which the complex promotes transport not defined","Direct GTPase interactions shown only in two-hybrid, not biochemically validated here"]},{"year":2001,"claim":"Showed Yif1p is selectively packaged into COPII vesicles, placing it physically in the ER-derived transport carriers rather than only at static membranes.","evidence":"Purification of COPII vesicles with MALDI mass spectrometry and antibody localization","pmids":["11157978"],"confidence":"Medium","gaps":["Single study","Does not establish a functional role within the vesicle"]},{"year":2002,"claim":"Demonstrated that Yif1p binds Rab/Ypt GTPases in a prenylation-dependent manner and associates with other YIP1-family members, linking it mechanistically to GTPase-controlled trafficking.","evidence":"In vitro biochemical binding assays and sequence analysis","pmids":["11943201"],"confidence":"Medium","gaps":["In vitro only","Functional consequence of GTPase binding unresolved"]},{"year":2003,"claim":"Resolved the step at which the complex acts: the Yip1p–Yif1p complex confers fusion competence on ER-derived vesicles and binds the SNAREs Bos1p and Sec22p, distinguishing vesicle fusion from vesicle budding/packaging.","evidence":"Reconstituted in vitro ER-to-Golgi transport assay with timed antibody inhibition and co-IP of SNARE partners","pmids":["12657649"],"confidence":"High","gaps":["Molecular mechanism by which the complex activates SNARE-mediated fusion not defined","No structural model of the complex–SNARE interaction"]},{"year":2003,"claim":"Identified Btn2p-dependent retrieval as the route maintaining Yif1p Golgi localization, addressing how the protein is recycled rather than degraded.","evidence":"Yeast two-hybrid, BTN2 deletion, and fluorescence localization","pmids":["12615067"],"confidence":"Medium","gaps":["Single lab","Mechanism of retrieval not detailed beyond Btn2p requirement"]},{"year":2004,"claim":"Mapped the cytoplasmic N-terminal domain as an interaction hub for PX-domain proteins, with the protein-binding surface distinct from the lipid-binding pocket.","evidence":"Genome-wide yeast two-hybrid screen and in vitro binding with domain dissection","pmids":["15263065"],"confidence":"Medium","gaps":["Functional significance of PX-domain interactions in vivo unresolved","Single study"]},{"year":2005,"claim":"Expanded the complex to a third essential subunit, Yos1p, refining the composition of the trafficking module required for ER-to-Golgi transport.","evidence":"Co-IP, subcellular fractionation, COPII packaging assay, and genetic depletion","pmids":["15659647"],"confidence":"High","gaps":["Stoichiometry of the Yip1p–Yif1p–Yos1p complex not determined","Specific contribution of Yos1p to fusion not isolated"]},{"year":2005,"claim":"Translated the yeast paradigm to humans, showing YIF1A localizes to the Golgi, binds human Yip1A, and depends on Yip1A for its Golgi localization.","evidence":"Immunofluorescence, yeast two-hybrid, co-IP, and dominant-negative overexpression","pmids":["15990086"],"confidence":"Medium","gaps":["Functional trafficking role of human YIF1A not directly tested here","Single lab"]},{"year":2006,"claim":"Detailed the endosome-to-Golgi retrieval pathway for Yif1p, implicating retromer/sorting-nexin machinery (Ypt6, Snx4, Vps26) alongside Btn2p.","evidence":"Co-IP, GST binding, GFP fluorescence, and genetic epistasis across multiple deletions","pmids":["17101785"],"confidence":"High","gaps":["Relevance of this retrieval route to mammalian YIF1A unknown"]},{"year":2013,"claim":"Defined a neuronal role: YIF1A occupies the ERGIC, recycles between ER and Golgi, and interacts with VAPB via transmembrane regions to support dendritic membrane trafficking, with the ALS8 VAPB-P56S mutant sequestering YIF1A into ER inclusions.","evidence":"Reciprocal co-IP, neuronal immunofluorescence, live imaging, siRNA knockdown, and dominant-negative overexpression","pmids":["23736259"],"confidence":"High","gaps":["Whether YIF1A mislocalization is causal in ALS8 pathology not established","Cargo selectivity of dendritic trafficking not mapped"]},{"year":2013,"claim":"Showed that YIF1A function is dissociable from Yip1A's ER-shaping activity, since YIF1A knockdown does not produce the ER whorls caused by Yip1A depletion.","evidence":"siRNA knockdown with ER-morphology fluorescence readout","pmids":["23342155"],"confidence":"Medium","gaps":["Negative finding; single lab","Does not define YIF1A's positive contribution to ER structure"]},{"year":2018,"claim":"Provided in vivo developmental evidence that the Yif1–Yip1 complex maintains Golgi integrity and ER-to-Golgi transport required for dendrite pruning, via downregulation of the adhesion molecule Neuroglian.","evidence":"Drosophila clonal genetic screen, co-IP in S2 cells, live imaging, and epistasis with Rab1 and Sar1","pmids":["29769219"],"confidence":"High","gaps":["Direct molecular link from transport defect to Neuroglian endocytosis not fully resolved","Mammalian YIF1A counterpart of this developmental role untested"]},{"year":null,"claim":"How human YIF1A mechanistically confers vesicle fusion competence and selects cargo for dendritic delivery, and whether its displacement by VAPB-P56S is causal in disease, remains unresolved.","evidence":"No direct experimental resolution in the available corpus","pmids":[],"confidence":"Low","gaps":["No structural model of the human YIF1A–Yip1A complex","Direct cargo repertoire of human YIF1A undefined","Causality of YIF1A in ALS8 not demonstrated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,7]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,3,5]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[0,5,8,11]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,5,11]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[1,3,11]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,3,16]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[3,11]}],"complexes":["Yip1p–Yif1p–Yos1p complex"],"partners":["YIPF1A/YIP1P","VAPB","BOS1P","SEC22P","YOS1P","YPT1P"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O95070","full_name":"Protein YIF1A","aliases":["54TMp","YIP1-interacting factor homolog A"],"length_aa":293,"mass_kda":32.0,"function":"Possible role in transport between endoplasmic reticulum and Golgi","subcellular_location":"Endoplasmic reticulum membrane; Golgi apparatus membrane; Endoplasmic reticulum-Golgi intermediate compartment membrane","url":"https://www.uniprot.org/uniprotkb/O95070/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/YIF1A","classification":"Not Classified","n_dependent_lines":16,"n_total_lines":1208,"dependency_fraction":0.013245033112582781},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"YIPF5","stoichiometry":10.0},{"gene":"COPE","stoichiometry":0.2},{"gene":"HSPA4","stoichiometry":0.2},{"gene":"SEC24C","stoichiometry":0.2},{"gene":"TMED10","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/YIF1A","total_profiled":1310},"omim":[{"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":"Enhanced","locations":[{"location":"Golgi apparatus","reliability":"Enhanced"},{"location":"Vesicles","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/YIF1A"},"hgnc":{"alias_symbol":["YIF1P","54TM","FinGER7"],"prev_symbol":["YIF1"]},"alphafold":{"accession":"O95070","domains":[{"cath_id":"-","chopping":"139-288","consensus_level":"high","plddt":87.3517,"start":139,"end":288}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O95070","model_url":"https://alphafold.ebi.ac.uk/files/AF-O95070-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O95070-F1-predicted_aligned_error_v6.png","plddt_mean":73.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=YIF1A","jax_strain_url":"https://www.jax.org/strain/search?query=YIF1A"},"sequence":{"accession":"O95070","fasta_url":"https://rest.uniprot.org/uniprotkb/O95070.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O95070/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O95070"}},"corpus_meta":[{"pmid":"11157978","id":"PMC_11157978","title":"Erv41p and Erv46p: 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Yip1p on Golgi membranes; the hydrophilic N-terminal half of Yif1p faces the cytosol and can interact with transport GTPases Ypt1p, Ypt31p, and Sec4p in two-hybrid analyses. Loss of Yif1p function in conditional-lethal mutants causes a block of ER-to-Golgi protein transport and accumulation of ER membranes and 40–50 nm vesicles. Genetic analyses suggest Yif1p acts downstream of Yip1p.\",\n      \"method\": \"Yeast two-hybrid, protein affinity studies, conditional-lethal mutant analysis, electron microscopy\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (two-hybrid, genetic epistasis, morphological phenotype) in a focused study of the yeast ortholog\",\n      \"pmids\": [\"10970842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Yif1p (yeast ortholog) is selectively and efficiently packaged into COPII vesicles, establishing its presence in ER-derived transport vesicles.\",\n      \"method\": \"Purification of COPII vesicles followed by MALDI mass spectrometry and antibody-based localization\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mass spectrometry identification on purified vesicles plus antibody verification, single study\",\n      \"pmids\": [\"11157978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Yif1p is a Yip1p-related protein that biochemically interacts with a variety of Rab/Ypt GTPases in a manner dependent on C-terminal prenylation of the GTPases, and physically associates with other YIP1 family members.\",\n      \"method\": \"In vitro biochemical binding assays, sequence analysis\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding assays with prenylation-dependence test, single lab\",\n      \"pmids\": [\"11943201\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The Yip1p–Yif1p complex is required for fusion competence of ER-derived vesicles with the Golgi in vitro. Anti-Yif1p antibodies added before vesicle budding block membrane fusion without affecting packaging of Yif1p, Yip1p, or SNAREs into vesicles. The Yip1p–Yif1p complex binds ER-to-Golgi SNAREs Bos1p and Sec22p.\",\n      \"method\": \"In vitro ER-to-Golgi transport assay with antibody inhibition; co-immunoprecipitation of SNARE binding partners\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted cell-free fusion assay plus co-IP of SNARE partners, rigorous epistatic placement of antibody addition timing\",\n      \"pmids\": [\"12657649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Btn2p interacts with Yif1p (yeast ortholog) and is required for its correct localization; deletion of BTN2 results in mislocalization of Yif1p to the vacuole, demonstrating Btn2p-dependent retrieval of Yif1p to the Golgi.\",\n      \"method\": \"Yeast two-hybrid, genetic deletion, fluorescence localization\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two-hybrid plus deletion phenotype with localization readout, single lab\",\n      \"pmids\": [\"12615067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Human YIF1A (HsYif1) belongs to a five-pass transmembrane protein family (FinGERs) that localizes to the Golgi apparatus and ER; overexpression of certain family members causes Golgi fragmentation, and family members interact with each other in yeast two-hybrid analyses.\",\n      \"method\": \"Immunofluorescence localization, yeast two-hybrid, overexpression phenotype\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — localization confirmed by immunofluorescence, overexpression phenotype observed, two-hybrid interactions; multiple orthogonal observations but limited functional mechanistic depth\",\n      \"pmids\": [\"14680843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The N-terminal cytoplasmic domain of Yif1p mediates interactions with PX domain-containing proteins (Grd19p, Vam7p, Vps17p, Ypt35p) as determined by two-hybrid and in vitro binding assays. A lipid-binding mutation in Ypt35p does not affect its protein interaction with Yif1p, indicating the protein-binding surface is distinct from the lipid-binding pocket.\",\n      \"method\": \"Yeast two-hybrid genome-wide screen; in vitro binding assays\",\n      \"journal\": \"Molecular & cellular proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two-hybrid plus in vitro binding with domain dissection, single study\",\n      \"pmids\": [\"15263065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Yos1p is a novel subunit of the Yip1p–Yif1p complex; it localizes to ER and Golgi membranes, is packaged into COPII vesicles, and associates with both Yip1p and Yif1p. Yos1p is essential and its depletion blocks ER-to-Golgi transport.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, COPII vesicle packaging assay, genetic depletion\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP, vesicle packaging assay, and loss-of-function phenotype in multiple orthogonal experiments\",\n      \"pmids\": [\"15659647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Human YIF1A (HsYif1) co-distributes with the Golgi marker GS27; it interacts with human Yip1A (HsYip1A) by yeast two-hybrid and immunoprecipitation; overexpression of a cytosolic-region-deleted mutant of HsYip1A disrupts YIF1A localization to the Golgi, showing that HsYip1A specifies YIF1A Golgi localization.\",\n      \"method\": \"Immunofluorescence, yeast two-hybrid, co-immunoprecipitation, dominant-negative overexpression\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction confirmed by two methods (two-hybrid + co-IP) and localization disruption by dominant-negative; single lab\",\n      \"pmids\": [\"15990086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Btn2p (a Hook1 ortholog) facilitates retrieval of Yif1p from late endosomes back to the Golgi; deletion of BTN2 blocks Yif1p retrieval and results in Yif1p delivery to the vacuole. Similar mislocalization occurs in ypt6Δ, snx4Δ, and vps26Δ strains.\",\n      \"method\": \"Immunoprecipitation, in vitro GST-binding assay, fluorescence microscopy with GFP-tagged proteins, genetic deletion analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP, in vitro binding, fluorescence localization, and genetic epistasis across multiple deletion backgrounds\",\n      \"pmids\": [\"17101785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Yif1B (a mammalian paralog closely related to YIF1A) interacts with the C-terminal domain of the 5-HT1A serotonin receptor and is required for targeting of 5-HT1A to distal dendrites; siRNA knockdown of Yif1B prevents dendritic addressing of 5-HT1A without affecting other receptors (sst2A, P2X2, 5-HT3A). Yif1B colocalizes with 5-HT1A in small trafficking vesicles.\",\n      \"method\": \"Yeast two-hybrid, GST pull-down from brain extracts and transfected cells, siRNA knockdown, immunofluorescence colocalization\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — note this is Yif1B (paralog), not YIF1A itself; included because it is the closest mammalian paralog and HGNC aliases include YIF1; multiple orthogonal methods, single lab\",\n      \"pmids\": [\"18685031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"YIF1A interacts with VAPB via transmembrane regions; YIF1A localizes to ER-Golgi intermediate compartments (ERGICs) in rat hippocampal neurons, recycles between ER and Golgi. VAPB is required for membrane trafficking into dendrites and normal dendritic morphology. The ALS8-linked VAPB-P56S mutant recruits YIF1A to its ER-like clusters, displacing YIF1A from its ERGIC localization.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence localization in neurons, live imaging, siRNA knockdown, dominant-negative overexpression\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, neuronal localization, loss-of-function trafficking phenotype, and pathological mutant displacement, multiple orthogonal methods in one study\",\n      \"pmids\": [\"23736259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"YIF1A knockdown does not cause ER whorl formation (a phenotype caused by Yip1A depletion), demonstrating that Yip1A's ability to regulate ER structure can be uncoupled from its interaction with YIF1A.\",\n      \"method\": \"siRNA knockdown, fluorescence microscopy for ER morphology\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean knockdown with defined morphological readout, single lab, result is a negative finding informative for pathway dissection\",\n      \"pmids\": [\"23342155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"YIF1A was identified as an interactor of tumor protein TPD52 and TPD52L1 in a low-stringency yeast two-hybrid screen.\",\n      \"method\": \"Yeast two-hybrid screen\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single two-hybrid identification, not validated by orthogonal method for YIF1A specifically\",\n      \"pmids\": [\"24604726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"GFP-tagged Yif1 (yeast) serves as a model Golgi quality-control substrate that is targeted to the vacuole upon amino acid starvation and TOR inactivation in a process dependent on ubiquitination by the DSC complex (including Tul1 E3 ligase) and upregulation of the VPS/ESCRT pathway via proteasome-mediated degradation of ESCRT-0.\",\n      \"method\": \"Fluorescence microscopy, genetic screens, deletion analysis, epistasis experiments\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with multiple deletions and pharmacological treatments, single lab\",\n      \"pmids\": [\"26344761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"YIPF1 and YIPF2 (mammalian Yif1p homologs, distinct from YIF1A) localize to medial-/trans-Golgi; YIPF6 forms stable complexes separately with YIPF1 and YIPF2 and is required for their stable expression. Knockdown of YIPF1 and YIPF2 delays Golgi reassembly after BFA washout and reduces intracellular glycan levels.\",\n      \"method\": \"Immunofluorescence, co-immunoprecipitation, siRNA knockdown, brefeldin A reassembly assay, glycan analysis\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — note these are YIPF1/YIPF2 paralogs not YIF1A; included for context of the YIF1A family; multiple orthogonal methods, single lab\",\n      \"pmids\": [\"28286305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Drosophila Yif1 forms a protein complex with Yip1 in S2 cells and ddaC neurons, colocalizes with Yip1 on ER/Golgi, and is required for integrity of the Golgi apparatus and Golgi outposts. Loss of Yif1 blocks dendrite pruning of ddaC sensory neurons during metamorphosis by impairing ER-to-Golgi transport, which in turn prevents endocytosis and downregulation of the cell-adhesion molecule Neuroglian.\",\n      \"method\": \"Clonal genetic screen, co-immunoprecipitation in S2 cells, immunofluorescence, live imaging, genetic epistasis with Rab1 and Sar1\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP, in vivo loss-of-function with defined cellular phenotype, genetic epistasis with known ER-Golgi regulators, Drosophila ortholog study\",\n      \"pmids\": [\"29769219\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"YIF1A is an integral multi-pass transmembrane protein that localizes primarily to the ER-Golgi intermediate compartment (ERGIC) and Golgi apparatus, where it forms a stable complex with Yip1A (via transmembrane regions) and participates in COPII vesicle-mediated ER-to-Golgi transport by establishing fusion competence of ER-derived vesicles through interaction with ER-Golgi SNAREs; in neurons, YIF1A is required for membrane trafficking into dendrites, and its ERGIC localization is disrupted by the ALS8-linked VAPB-P56S mutation, which sequesters YIF1A into ER-like inclusions.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"YIF1A is an integral multi-pass transmembrane protein of the ER–Golgi system that functions in COPII-dependent ER-to-Golgi membrane transport, characterized largely through its yeast ortholog Yif1p [#0, #3]. Yif1p forms a tight, stable complex with the YIP1-family protein Yip1p, acting downstream of Yip1p; loss of Yif1p function blocks ER-to-Golgi protein transport and causes accumulation of ER membranes and 40–50 nm vesicles [#0]. This complex, together with the additional subunit Yos1p, is efficiently packaged into COPII vesicles and is required for the fusion competence of ER-derived vesicles with the Golgi, an activity it confers in part through binding the ER-to-Golgi SNAREs Bos1p and Sec22p [#1, #3, #7]. The cytosolic N-terminal domain interacts with transport Rab/Ypt GTPases in a prenylation-dependent manner, coupling the complex to vesicle-trafficking GTPases [#0, #2]. The human protein localizes to the Golgi and ER and belongs to a five-pass transmembrane (FinGER/YIPF) family whose members interact with one another and whose overexpression fragments the Golgi [#5]; human YIF1A binds human Yip1A, which specifies its Golgi localization [#8]. In neurons, YIF1A localizes to the ER–Golgi intermediate compartment, recycles between ER and Golgi, and interacts via its transmembrane regions with VAPB to support membrane trafficking into dendrites; the ALS8-linked VAPB-P56S mutant sequesters YIF1A into ER-like inclusions, displacing it from the ERGIC [#11]. YIF1A function is separable from Yip1A's role in regulating ER structure, since YIF1A knockdown does not reproduce the ER whorl phenotype of Yip1A depletion [#12].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established that Yif1p partners with Yip1p and is functionally required for ER-to-Golgi transport, defining the gene's core trafficking role and its epistatic position downstream of Yip1p.\",\n      \"evidence\": \"Yeast two-hybrid, affinity studies, conditional-lethal mutants, and electron microscopy of the yeast ortholog\",\n      \"pmids\": [\"10970842\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which the complex promotes transport not defined\", \"Direct GTPase interactions shown only in two-hybrid, not biochemically validated here\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Showed Yif1p is selectively packaged into COPII vesicles, placing it physically in the ER-derived transport carriers rather than only at static membranes.\",\n      \"evidence\": \"Purification of COPII vesicles with MALDI mass spectrometry and antibody localization\",\n      \"pmids\": [\"11157978\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single study\", \"Does not establish a functional role within the vesicle\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Demonstrated that Yif1p binds Rab/Ypt GTPases in a prenylation-dependent manner and associates with other YIP1-family members, linking it mechanistically to GTPase-controlled trafficking.\",\n      \"evidence\": \"In vitro biochemical binding assays and sequence analysis\",\n      \"pmids\": [\"11943201\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vitro only\", \"Functional consequence of GTPase binding unresolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Resolved the step at which the complex acts: the Yip1p–Yif1p complex confers fusion competence on ER-derived vesicles and binds the SNAREs Bos1p and Sec22p, distinguishing vesicle fusion from vesicle budding/packaging.\",\n      \"evidence\": \"Reconstituted in vitro ER-to-Golgi transport assay with timed antibody inhibition and co-IP of SNARE partners\",\n      \"pmids\": [\"12657649\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which the complex activates SNARE-mediated fusion not defined\", \"No structural model of the complex–SNARE interaction\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identified Btn2p-dependent retrieval as the route maintaining Yif1p Golgi localization, addressing how the protein is recycled rather than degraded.\",\n      \"evidence\": \"Yeast two-hybrid, BTN2 deletion, and fluorescence localization\",\n      \"pmids\": [\"12615067\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanism of retrieval not detailed beyond Btn2p requirement\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Mapped the cytoplasmic N-terminal domain as an interaction hub for PX-domain proteins, with the protein-binding surface distinct from the lipid-binding pocket.\",\n      \"evidence\": \"Genome-wide yeast two-hybrid screen and in vitro binding with domain dissection\",\n      \"pmids\": [\"15263065\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional significance of PX-domain interactions in vivo unresolved\", \"Single study\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Expanded the complex to a third essential subunit, Yos1p, refining the composition of the trafficking module required for ER-to-Golgi transport.\",\n      \"evidence\": \"Co-IP, subcellular fractionation, COPII packaging assay, and genetic depletion\",\n      \"pmids\": [\"15659647\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of the Yip1p–Yif1p–Yos1p complex not determined\", \"Specific contribution of Yos1p to fusion not isolated\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Translated the yeast paradigm to humans, showing YIF1A localizes to the Golgi, binds human Yip1A, and depends on Yip1A for its Golgi localization.\",\n      \"evidence\": \"Immunofluorescence, yeast two-hybrid, co-IP, and dominant-negative overexpression\",\n      \"pmids\": [\"15990086\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional trafficking role of human YIF1A not directly tested here\", \"Single lab\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Detailed the endosome-to-Golgi retrieval pathway for Yif1p, implicating retromer/sorting-nexin machinery (Ypt6, Snx4, Vps26) alongside Btn2p.\",\n      \"evidence\": \"Co-IP, GST binding, GFP fluorescence, and genetic epistasis across multiple deletions\",\n      \"pmids\": [\"17101785\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relevance of this retrieval route to mammalian YIF1A unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined a neuronal role: YIF1A occupies the ERGIC, recycles between ER and Golgi, and interacts with VAPB via transmembrane regions to support dendritic membrane trafficking, with the ALS8 VAPB-P56S mutant sequestering YIF1A into ER inclusions.\",\n      \"evidence\": \"Reciprocal co-IP, neuronal immunofluorescence, live imaging, siRNA knockdown, and dominant-negative overexpression\",\n      \"pmids\": [\"23736259\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether YIF1A mislocalization is causal in ALS8 pathology not established\", \"Cargo selectivity of dendritic trafficking not mapped\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed that YIF1A function is dissociable from Yip1A's ER-shaping activity, since YIF1A knockdown does not produce the ER whorls caused by Yip1A depletion.\",\n      \"evidence\": \"siRNA knockdown with ER-morphology fluorescence readout\",\n      \"pmids\": [\"23342155\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Negative finding; single lab\", \"Does not define YIF1A's positive contribution to ER structure\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Provided in vivo developmental evidence that the Yif1–Yip1 complex maintains Golgi integrity and ER-to-Golgi transport required for dendrite pruning, via downregulation of the adhesion molecule Neuroglian.\",\n      \"evidence\": \"Drosophila clonal genetic screen, co-IP in S2 cells, live imaging, and epistasis with Rab1 and Sar1\",\n      \"pmids\": [\"29769219\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular link from transport defect to Neuroglian endocytosis not fully resolved\", \"Mammalian YIF1A counterpart of this developmental role untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How human YIF1A mechanistically confers vesicle fusion competence and selects cargo for dendritic delivery, and whether its displacement by VAPB-P56S is causal in disease, remains unresolved.\",\n      \"evidence\": \"No direct experimental resolution in the available corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of the human YIF1A–Yip1A complex\", \"Direct cargo repertoire of human YIF1A undefined\", \"Causality of YIF1A in ALS8 not demonstrated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 7]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 3, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [0, 5, 8, 11]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 5, 11]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [1, 3, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 3, 16]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [3, 11]}\n    ],\n    \"complexes\": [\"Yip1p\\u2013Yif1p\\u2013Yos1p complex\"],\n    \"partners\": [\"YIPF1A/Yip1p\", \"VAPB\", \"Bos1p\", \"Sec22p\", \"Yos1p\", \"Ypt1p\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}