{"gene":"YIF1B","run_date":"2026-04-28T23:00:23","timeline":{"discoveries":[{"year":2008,"finding":"YIF1B (Yif1B) was identified as a direct binding partner of the 5-HT1A serotonin receptor (5-HT1AR) C-terminal domain (17 aa region), confirmed by yeast two-hybrid, GST pull-down from rat brain extracts and transfected cell lines. siRNA-mediated knockdown of Yif1B in primary neurons specifically prevented dendritic targeting of 5-HT1AR without affecting other receptors (sst2A, P2X2, 5-HT3A), establishing Yif1B as a key mediator of ER/Golgi trafficking machinery required for somatodendritic receptor sorting.","method":"Yeast two-hybrid screen, GST pull-down (rat brain extracts and transfected cells), siRNA knockdown in primary neurons with receptor localization readout","journal":"The Journal of Neuroscience","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (Y2H, GST pull-down, siRNA KD with specific receptor targeting phenotype), replicated in two experimental systems","pmids":["18685031"],"is_preprint":false},{"year":2012,"finding":"YIF1B binds directly to a tribasic motif in the C-tail of 5-HT1AR with high affinity (KD ≈ 37 nM), determined by directed mutagenesis, GST pull-down, and surface plasmon resonance. YIF1B acts as a scaffold protein assembling a vesicular complex containing Yip1A, Rab6, and Kif5B (motor protein), which is required for dendritic targeting of 5-HT1AR. Live videomicroscopy showed co-trafficking of 5-HT1AR, Yif1B, Yip1A, and Rab6 in vesicles moving bidirectionally from soma into the dendritic tree.","method":"Directed mutagenesis, GST pull-down, surface plasmon resonance, live videomicroscopy, siRNA knockdown","journal":"The Journal of Neuroscience","confidence":"High","confidence_rationale":"Tier 1–2 — direct binding affinity measured by SPR, mutagenesis of binding motif, live imaging of complex trafficking; strong orthogonal evidence","pmids":["23055492"],"is_preprint":false},{"year":2015,"finding":"Yif1B localizes to the intermediate compartment (IC) rather than the Golgi itself. Yif1B depletion in HeLa cells accelerated anterograde traffic of the VSVG marker, as did Yif1B KO in hippocampal neurons, while retrograde ShTx traffic was unaffected. Long-term Yif1B depletion (Yif1B KO mice) caused disorganized Golgi architecture in CA1 pyramidal neurons confirmed by electron microscopy, indicating Yif1B regulates anterograde ER-to-Golgi trafficking by shuttling between ER, IC, and Golgi compartments.","method":"VSVG trafficking assay in HeLa cells and Yif1B KO neurons, retrograde ShTx assay, immunofluorescence localization, electron microscopy of Yif1B KO mouse brain","journal":"Traffic","confidence":"High","confidence_rationale":"Tier 2 — directional trafficking assays with orthogonal cargo controls, KO model with ultrastructural validation","pmids":["26077767"],"is_preprint":false},{"year":2019,"finding":"YIF1B was identified as an interactor of the lysosomal ABC transporter TAPL via interactome (mass spectrometry-based) analysis. YIF1B interacts with TAPL through its transmembrane domain, specifically engaging the TMD0 of TAPL, and this interaction depends on a salt bridge (Asp-17/Arg-57) within TMD0. YIF1B is involved in ER-to-Golgi trafficking of TAPL, as YIF1B knockdown disrupts this step.","method":"Interactome analysis (mass spectrometry), co-immunoprecipitation, RUSH assay (synchronized trafficking), immunostaining, siRNA knockdown","journal":"The Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 — interactome + domain mapping + trafficking assay, but single study for this specific interaction","pmids":["30877195"],"is_preprint":false},{"year":2020,"finding":"Biallelic loss-of-function mutations in YIF1B in humans and Yif1B KO in mice cause primary cilia abnormalities in skin fibroblasts and ciliary architectural defects in the brain, despite YIF1B not being detected within primary cilia itself. This establishes that YIF1B's role in anterograde ER-to-Golgi/membrane trafficking indirectly supports primary cilia structure, linking Golgipathies to ciliopathies through a trafficking mechanism.","method":"Patient fibroblast analysis, Yif1B KO mouse model, immunofluorescence, electron microscopy, MRI","journal":"Brain","confidence":"Medium","confidence_rationale":"Tier 2 — KO model plus patient cells with consistent phenotype, mechanistic link through trafficking pathway, single study","pmids":["33103737"],"is_preprint":false},{"year":2020,"finding":"Yif1B KO mice show decreased forebrain density of 5-HT projection fibres, hypofunctionality of 5-HT1A autoreceptors on raphe neurons, reduced social interaction, and loss of antidepressant-like response to acute fluoxetine, establishing Yif1B as functionally required for proper 5-HT1AR autoreceptor activity and serotonin homeostasis in vivo.","method":"Yif1B KO mouse model, receptor autoradiography, behavioral assays (social interaction, forced swim/tail suspension), fluoxetine challenge","journal":"Journal of Psychiatry & Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — defined KO phenotype with multiple neurobiological readouts, single study","pmids":["32459080"],"is_preprint":false},{"year":2024,"finding":"YIF1B directly translocates unglycosylated SARS-CoV-2 ORF8 into vesicles mediating unconventional secretion; the α4 helix of YIF1B interacts with the β8 sheet of ORF8. YIF1B knockdown in cell/hamster models blocked ORF8 unconventional secretion, attenuated inflammation, and reduced mortality, identifying YIF1B as the molecular translocator for this unconventional secretory pathway.","method":"Mass spectrometry, gene knockout/knockdown in cell and hamster models, domain interaction mapping (α4 helix/β8 sheet), inflammatory readout, survival assay","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 — KO/KD with domain-level interaction mapping and functional in vivo readout; single study for this novel substrate","pmids":["39811650"],"is_preprint":false}],"current_model":"YIF1B is an intracellular membrane-bound scaffold protein of the intermediate compartment/ER-Golgi interface that mediates anterograde protein trafficking: it binds directly (via its transmembrane domain) to specific motifs in cargo proteins such as the 5-HT1A receptor C-tail and TAPL TMD0, recruits trafficking partners (Yip1A, Rab6, Kif5B), and transports cargo-containing vesicles along microtubules to specific destinations including neuronal dendrites and lysosomes; loss of YIF1B disrupts Golgi architecture, primary cilia, serotonergic neurotransmission, and 5-HT1AR autoreceptor function in vivo."},"narrative":{"teleology":[{"year":2008,"claim":"Identifying YIF1B as a direct interactor of the 5-HT1A receptor C-tail established it as a trafficking factor required for somatodendritic receptor sorting, answering how 5-HT1AR reaches dendrites selectively.","evidence":"Yeast two-hybrid, GST pull-down from rat brain, and siRNA knockdown in primary neurons showing selective loss of dendritic 5-HT1AR","pmids":["18685031"],"confidence":"High","gaps":["Binding domain on YIF1B not mapped","Mechanism by which YIF1B selects 5-HT1AR over other dendritic receptors unknown","No in vivo validation of dendritic targeting defect"]},{"year":2012,"claim":"Defining the tribasic motif–YIF1B interaction at nanomolar affinity and identifying the Yip1A/Rab6/Kif5B vesicular complex resolved the molecular mechanism by which YIF1B scaffolds cargo for microtubule-based dendritic transport.","evidence":"Surface plasmon resonance (KD ~37 nM), directed mutagenesis, live videomicroscopy of co-trafficking vesicles in neurons","pmids":["23055492"],"confidence":"High","gaps":["Structural basis of scaffold assembly not resolved","Whether Rab6 or Kif5B bind YIF1B directly or via Yip1A unclear","Stoichiometry of the vesicular complex unknown"]},{"year":2015,"claim":"Localizing YIF1B to the intermediate compartment and showing that its loss accelerates anterograde but not retrograde traffic — while disorganizing Golgi ultrastructure — established YIF1B as a rate-limiting regulator of ER-to-Golgi transport rather than a general trafficking factor.","evidence":"VSVG and ShTx directional trafficking assays in HeLa cells and KO neurons; electron microscopy of KO mouse CA1 neurons","pmids":["26077767"],"confidence":"High","gaps":["How accelerated anterograde flow leads to Golgi disorganization is mechanistically unclear","Whether YIF1B acts as a checkpoint or a sorting factor at the IC not distinguished"]},{"year":2019,"claim":"Demonstrating that YIF1B engages TAPL's TMD0 via a transmembrane salt bridge broadened YIF1B's cargo repertoire beyond GPCRs and revealed transmembrane domain–mediated recognition as a general cargo-binding mechanism.","evidence":"Mass spectrometry interactome, co-immunoprecipitation, RUSH synchronized trafficking assay, siRNA knockdown","pmids":["30877195"],"confidence":"Medium","gaps":["Single study for TAPL interaction; independent replication pending","Whether the TMD-based and C-tail-based cargo recognition modes are mutually exclusive or simultaneous unknown","Functional consequence of impaired TAPL trafficking on lysosomal peptide transport not tested"]},{"year":2020,"claim":"Linking biallelic YIF1B loss-of-function in humans and KO mice to primary cilia defects and Golgi disorganization established YIF1B deficiency as a Golgipathy-ciliopathy and connected intracellular trafficking to cilia maintenance, while parallel work showed KO mice have impaired 5-HT1A autoreceptor function, reduced serotonergic innervation, and loss of SSRI responsiveness.","evidence":"Patient fibroblasts plus KO mouse cilia/brain EM and MRI (PMID:33103737); KO mouse autoradiography, behavioral assays, fluoxetine challenge (PMID:32459080)","pmids":["33103737","32459080"],"confidence":"Medium","gaps":["Both are single studies; replication in independent cohorts needed","Molecular pathway from Golgi disorganization to cilia defects not delineated","Whether 5-HT1AR mistrafficking fully accounts for the behavioral phenotype unclear"]},{"year":2024,"claim":"Identifying YIF1B as the translocator that loads unglycosylated SARS-CoV-2 ORF8 into unconventional secretory vesicles revealed an unexpected role for YIF1B in unconventional protein secretion and viral pathogenesis.","evidence":"Mass spectrometry, domain interaction mapping (α4 helix/β8 sheet), KO/KD in cell and hamster models with inflammatory and survival readouts","pmids":["39811650"],"confidence":"Medium","gaps":["Single study; mechanism of translocation across the vesicle membrane not resolved","Whether YIF1B mediates unconventional secretion of endogenous substrates unknown","Generalizability to other viral proteins not tested"]},{"year":null,"claim":"A structural model of YIF1B — alone and in complex with its cargoes and scaffold partners — is needed to unify the dual cargo-recognition modes (C-tail tribasic motif vs. TMD-based) and to explain how YIF1B gates anterograde trafficking at the intermediate compartment.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of YIF1B available","Full repertoire of endogenous cargo beyond 5-HT1AR and TAPL unknown","Whether YIF1B plays a general role in unconventional secretion remains untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[3,6]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[2]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[2]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[1,6]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,1,2,3]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,1,3]}],"complexes":["Yif1B–Yip1A–Rab6–Kif5B vesicular trafficking complex"],"partners":["YIP1A","RAB6","KIF5B","HTR1A","TAPL"],"other_free_text":[]},"mechanistic_narrative":"YIF1B is an intermediate compartment (IC)-resident scaffold protein that regulates anterograde ER-to-Golgi trafficking by assembling cargo-containing vesicular complexes with Yip1A, Rab6, and the kinesin motor Kif5B, thereby directing specific transmembrane proteins to their correct subcellular destinations [PMID:23055492, PMID:26077767]. YIF1B engages cargo through its transmembrane domain, binding the C-terminal tribasic motif of the serotonin 5-HT1A receptor with nanomolar affinity and the TMD0 of the lysosomal transporter TAPL via a salt-bridge-dependent mechanism, and also translocates unglycosylated SARS-CoV-2 ORF8 into vesicles for unconventional secretion [PMID:23055492, PMID:30877195, PMID:39811650]. Loss of YIF1B disrupts Golgi architecture, causes primary cilia defects, impairs serotonergic neurotransmission with loss of 5-HT1A autoreceptor function and antidepressant responsiveness, and in humans biallelic loss-of-function mutations produce a neurodevelopmental syndrome linking Golgipathies to ciliopathies [PMID:26077767, PMID:33103737, PMID:32459080]."},"prefetch_data":{"uniprot":{"accession":"Q5BJH7","full_name":"Protein YIF1B","aliases":["YIP1-interacting factor homolog B"],"length_aa":314,"mass_kda":34.4,"function":"Functions in endoplasmic reticulum to Golgi vesicle-mediated transport and regulates the proper organization of the endoplasmic reticulum and the Golgi (By similarity). Plays a key role in targeting to neuronal dendrites receptors such as HTR1A (By similarity). Plays also a role in primary cilium and sperm flagellum assembly probably through protein transport to these compartments (PubMed:33103737)","subcellular_location":"Endoplasmic reticulum membrane; Golgi apparatus membrane; Endoplasmic reticulum-Golgi intermediate compartment membrane","url":"https://www.uniprot.org/uniprotkb/Q5BJH7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/YIF1B","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"YIPF5","stoichiometry":10.0},{"gene":"RAB1A","stoichiometry":0.2},{"gene":"RAB1B","stoichiometry":0.2},{"gene":"RER1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/YIF1B","total_profiled":1310},"omim":[{"mim_id":"619125","title":"KAYA-BARAKAT-MASSON SYNDROME; KABAMAS","url":"https://www.omim.org/entry/619125"},{"mim_id":"619109","title":"YIP1-INTERACTING FACTOR HOMOLOG B, MEMBRANE-TRAFFICKING PROTEIN; YIF1B","url":"https://www.omim.org/entry/619109"},{"mim_id":"605453","title":"ATP-BINDING CASSETTE, SUBFAMILY B, MEMBER 9; ABCB9","url":"https://www.omim.org/entry/605453"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Golgi apparatus","reliability":"Supported"},{"location":"Vesicles","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/YIF1B"},"hgnc":{"alias_symbol":["FinGER8"],"prev_symbol":[]},"alphafold":{"accession":"Q5BJH7","domains":[{"cath_id":"-","chopping":"153-311","consensus_level":"high","plddt":88.8919,"start":153,"end":311}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5BJH7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5BJH7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5BJH7-F1-predicted_aligned_error_v6.png","plddt_mean":73.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=YIF1B","jax_strain_url":"https://www.jax.org/strain/search?query=YIF1B"},"sequence":{"accession":"Q5BJH7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5BJH7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5BJH7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5BJH7"}},"corpus_meta":[{"pmid":"18685031","id":"PMC_18685031","title":"Targeting of the 5-HT1A serotonin receptor to neuronal dendrites is mediated by Yif1B.","date":"2008","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/18685031","citation_count":56,"is_preprint":false},{"pmid":"23055492","id":"PMC_23055492","title":"A new vesicular scaffolding complex mediates the G-protein-coupled 5-HT1A receptor targeting to neuronal dendrites.","date":"2012","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/23055492","citation_count":29,"is_preprint":false},{"pmid":"26077767","id":"PMC_26077767","title":"Yif1B Is Involved in the Anterograde Traffic Pathway and the Golgi Architecture.","date":"2015","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/26077767","citation_count":20,"is_preprint":false},{"pmid":"30877195","id":"PMC_30877195","title":"Lysosomal targeting of the ABC transporter TAPL is determined by membrane-localized charged residues.","date":"2019","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30877195","citation_count":19,"is_preprint":false},{"pmid":"34269122","id":"PMC_34269122","title":"Histopathology is required to identify and characterize myopathies in high-throughput phenotype screening of genetically engineered mice.","date":"2021","source":"Veterinary pathology","url":"https://pubmed.ncbi.nlm.nih.gov/34269122","citation_count":15,"is_preprint":false},{"pmid":"33103737","id":"PMC_33103737","title":"YIF1B mutations cause a post-natal neurodevelopmental syndrome associated with Golgi and primary cilium alterations.","date":"2020","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/33103737","citation_count":14,"is_preprint":false},{"pmid":"34052107","id":"PMC_34052107","title":"A 10-Gene Signature for Predicting the Response to Neoadjuvant Trastuzumab Therapy in HER2-Positive Breast Cancer.","date":"2021","source":"Clinical breast cancer","url":"https://pubmed.ncbi.nlm.nih.gov/34052107","citation_count":13,"is_preprint":false},{"pmid":"24467872","id":"PMC_24467872","title":"The effects of chronic ethanol self-administration on hippocampal 5-HT1A receptors in monkeys.","date":"2014","source":"Drug and alcohol dependence","url":"https://pubmed.ncbi.nlm.nih.gov/24467872","citation_count":12,"is_preprint":false},{"pmid":"32459080","id":"PMC_32459080","title":"Key role of the 5-HT1A receptor addressing protein Yif1B in serotonin neurotransmission and SSRI treatment.","date":"2020","source":"Journal of psychiatry & neuroscience : JPN","url":"https://pubmed.ncbi.nlm.nih.gov/32459080","citation_count":8,"is_preprint":false},{"pmid":"35363364","id":"PMC_35363364","title":"Identification of epilepsy concomitant candidate genes recognized in Saudi epileptic patients.","date":"2022","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35363364","citation_count":5,"is_preprint":false},{"pmid":"39878408","id":"PMC_39878408","title":"Transcriptome-Wide Association Study Identified Novel Blood Tissue Gene Biomarkers for Prostate Cancer Risk.","date":"2025","source":"The Prostate","url":"https://pubmed.ncbi.nlm.nih.gov/39878408","citation_count":3,"is_preprint":false},{"pmid":"36948290","id":"PMC_36948290","title":"YIF1B-related Kaya-Barakat-Masson Syndrome: Report of a new patient and literature review.","date":"2023","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36948290","citation_count":1,"is_preprint":false},{"pmid":"39811650","id":"PMC_39811650","title":"Yip1 interacting factor homolog B mediates the unconventional secretion of ORF8 during SARS-CoV-2 infection.","date":"2024","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/39811650","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8510,"output_tokens":2154,"usd":0.02892},"stage2":{"model":"claude-opus-4-6","input_tokens":5423,"output_tokens":2219,"usd":0.123885},"total_usd":0.152805,"stage1_batch_id":"msgbatch_01BparvgRZ9S2LMidvaoo86K","stage2_batch_id":"msgbatch_01NkBfv9SVZWthhS7j6mU6G3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"YIF1B (Yif1B) was identified as a direct binding partner of the 5-HT1A serotonin receptor (5-HT1AR) C-terminal domain (17 aa region), confirmed by yeast two-hybrid, GST pull-down from rat brain extracts and transfected cell lines. siRNA-mediated knockdown of Yif1B in primary neurons specifically prevented dendritic targeting of 5-HT1AR without affecting other receptors (sst2A, P2X2, 5-HT3A), establishing Yif1B as a key mediator of ER/Golgi trafficking machinery required for somatodendritic receptor sorting.\",\n      \"method\": \"Yeast two-hybrid screen, GST pull-down (rat brain extracts and transfected cells), siRNA knockdown in primary neurons with receptor localization readout\",\n      \"journal\": \"The Journal of Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Y2H, GST pull-down, siRNA KD with specific receptor targeting phenotype), replicated in two experimental systems\",\n      \"pmids\": [\"18685031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"YIF1B binds directly to a tribasic motif in the C-tail of 5-HT1AR with high affinity (KD ≈ 37 nM), determined by directed mutagenesis, GST pull-down, and surface plasmon resonance. YIF1B acts as a scaffold protein assembling a vesicular complex containing Yip1A, Rab6, and Kif5B (motor protein), which is required for dendritic targeting of 5-HT1AR. Live videomicroscopy showed co-trafficking of 5-HT1AR, Yif1B, Yip1A, and Rab6 in vesicles moving bidirectionally from soma into the dendritic tree.\",\n      \"method\": \"Directed mutagenesis, GST pull-down, surface plasmon resonance, live videomicroscopy, siRNA knockdown\",\n      \"journal\": \"The Journal of Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct binding affinity measured by SPR, mutagenesis of binding motif, live imaging of complex trafficking; strong orthogonal evidence\",\n      \"pmids\": [\"23055492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Yif1B localizes to the intermediate compartment (IC) rather than the Golgi itself. Yif1B depletion in HeLa cells accelerated anterograde traffic of the VSVG marker, as did Yif1B KO in hippocampal neurons, while retrograde ShTx traffic was unaffected. Long-term Yif1B depletion (Yif1B KO mice) caused disorganized Golgi architecture in CA1 pyramidal neurons confirmed by electron microscopy, indicating Yif1B regulates anterograde ER-to-Golgi trafficking by shuttling between ER, IC, and Golgi compartments.\",\n      \"method\": \"VSVG trafficking assay in HeLa cells and Yif1B KO neurons, retrograde ShTx assay, immunofluorescence localization, electron microscopy of Yif1B KO mouse brain\",\n      \"journal\": \"Traffic\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — directional trafficking assays with orthogonal cargo controls, KO model with ultrastructural validation\",\n      \"pmids\": [\"26077767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"YIF1B was identified as an interactor of the lysosomal ABC transporter TAPL via interactome (mass spectrometry-based) analysis. YIF1B interacts with TAPL through its transmembrane domain, specifically engaging the TMD0 of TAPL, and this interaction depends on a salt bridge (Asp-17/Arg-57) within TMD0. YIF1B is involved in ER-to-Golgi trafficking of TAPL, as YIF1B knockdown disrupts this step.\",\n      \"method\": \"Interactome analysis (mass spectrometry), co-immunoprecipitation, RUSH assay (synchronized trafficking), immunostaining, siRNA knockdown\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — interactome + domain mapping + trafficking assay, but single study for this specific interaction\",\n      \"pmids\": [\"30877195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Biallelic loss-of-function mutations in YIF1B in humans and Yif1B KO in mice cause primary cilia abnormalities in skin fibroblasts and ciliary architectural defects in the brain, despite YIF1B not being detected within primary cilia itself. This establishes that YIF1B's role in anterograde ER-to-Golgi/membrane trafficking indirectly supports primary cilia structure, linking Golgipathies to ciliopathies through a trafficking mechanism.\",\n      \"method\": \"Patient fibroblast analysis, Yif1B KO mouse model, immunofluorescence, electron microscopy, MRI\",\n      \"journal\": \"Brain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO model plus patient cells with consistent phenotype, mechanistic link through trafficking pathway, single study\",\n      \"pmids\": [\"33103737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Yif1B KO mice show decreased forebrain density of 5-HT projection fibres, hypofunctionality of 5-HT1A autoreceptors on raphe neurons, reduced social interaction, and loss of antidepressant-like response to acute fluoxetine, establishing Yif1B as functionally required for proper 5-HT1AR autoreceptor activity and serotonin homeostasis in vivo.\",\n      \"method\": \"Yif1B KO mouse model, receptor autoradiography, behavioral assays (social interaction, forced swim/tail suspension), fluoxetine challenge\",\n      \"journal\": \"Journal of Psychiatry & Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined KO phenotype with multiple neurobiological readouts, single study\",\n      \"pmids\": [\"32459080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YIF1B directly translocates unglycosylated SARS-CoV-2 ORF8 into vesicles mediating unconventional secretion; the α4 helix of YIF1B interacts with the β8 sheet of ORF8. YIF1B knockdown in cell/hamster models blocked ORF8 unconventional secretion, attenuated inflammation, and reduced mortality, identifying YIF1B as the molecular translocator for this unconventional secretory pathway.\",\n      \"method\": \"Mass spectrometry, gene knockout/knockdown in cell and hamster models, domain interaction mapping (α4 helix/β8 sheet), inflammatory readout, survival assay\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO/KD with domain-level interaction mapping and functional in vivo readout; single study for this novel substrate\",\n      \"pmids\": [\"39811650\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"YIF1B is an intracellular membrane-bound scaffold protein of the intermediate compartment/ER-Golgi interface that mediates anterograde protein trafficking: it binds directly (via its transmembrane domain) to specific motifs in cargo proteins such as the 5-HT1A receptor C-tail and TAPL TMD0, recruits trafficking partners (Yip1A, Rab6, Kif5B), and transports cargo-containing vesicles along microtubules to specific destinations including neuronal dendrites and lysosomes; loss of YIF1B disrupts Golgi architecture, primary cilia, serotonergic neurotransmission, and 5-HT1AR autoreceptor function in vivo.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"YIF1B is an intermediate compartment (IC)-resident scaffold protein that regulates anterograde ER-to-Golgi trafficking by assembling cargo-containing vesicular complexes with Yip1A, Rab6, and the kinesin motor Kif5B, thereby directing specific transmembrane proteins to their correct subcellular destinations [PMID:23055492, PMID:26077767]. YIF1B engages cargo through its transmembrane domain, binding the C-terminal tribasic motif of the serotonin 5-HT1A receptor with nanomolar affinity and the TMD0 of the lysosomal transporter TAPL via a salt-bridge-dependent mechanism, and also translocates unglycosylated SARS-CoV-2 ORF8 into vesicles for unconventional secretion [PMID:23055492, PMID:30877195, PMID:39811650]. Loss of YIF1B disrupts Golgi architecture, causes primary cilia defects, impairs serotonergic neurotransmission with loss of 5-HT1A autoreceptor function and antidepressant responsiveness, and in humans biallelic loss-of-function mutations produce a neurodevelopmental syndrome linking Golgipathies to ciliopathies [PMID:26077767, PMID:33103737, PMID:32459080].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Identifying YIF1B as a direct interactor of the 5-HT1A receptor C-tail established it as a trafficking factor required for somatodendritic receptor sorting, answering how 5-HT1AR reaches dendrites selectively.\",\n      \"evidence\": \"Yeast two-hybrid, GST pull-down from rat brain, and siRNA knockdown in primary neurons showing selective loss of dendritic 5-HT1AR\",\n      \"pmids\": [\"18685031\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Binding domain on YIF1B not mapped\",\n        \"Mechanism by which YIF1B selects 5-HT1AR over other dendritic receptors unknown\",\n        \"No in vivo validation of dendritic targeting defect\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defining the tribasic motif–YIF1B interaction at nanomolar affinity and identifying the Yip1A/Rab6/Kif5B vesicular complex resolved the molecular mechanism by which YIF1B scaffolds cargo for microtubule-based dendritic transport.\",\n      \"evidence\": \"Surface plasmon resonance (KD ~37 nM), directed mutagenesis, live videomicroscopy of co-trafficking vesicles in neurons\",\n      \"pmids\": [\"23055492\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of scaffold assembly not resolved\",\n        \"Whether Rab6 or Kif5B bind YIF1B directly or via Yip1A unclear\",\n        \"Stoichiometry of the vesicular complex unknown\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Localizing YIF1B to the intermediate compartment and showing that its loss accelerates anterograde but not retrograde traffic — while disorganizing Golgi ultrastructure — established YIF1B as a rate-limiting regulator of ER-to-Golgi transport rather than a general trafficking factor.\",\n      \"evidence\": \"VSVG and ShTx directional trafficking assays in HeLa cells and KO neurons; electron microscopy of KO mouse CA1 neurons\",\n      \"pmids\": [\"26077767\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How accelerated anterograde flow leads to Golgi disorganization is mechanistically unclear\",\n        \"Whether YIF1B acts as a checkpoint or a sorting factor at the IC not distinguished\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrating that YIF1B engages TAPL's TMD0 via a transmembrane salt bridge broadened YIF1B's cargo repertoire beyond GPCRs and revealed transmembrane domain–mediated recognition as a general cargo-binding mechanism.\",\n      \"evidence\": \"Mass spectrometry interactome, co-immunoprecipitation, RUSH synchronized trafficking assay, siRNA knockdown\",\n      \"pmids\": [\"30877195\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single study for TAPL interaction; independent replication pending\",\n        \"Whether the TMD-based and C-tail-based cargo recognition modes are mutually exclusive or simultaneous unknown\",\n        \"Functional consequence of impaired TAPL trafficking on lysosomal peptide transport not tested\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linking biallelic YIF1B loss-of-function in humans and KO mice to primary cilia defects and Golgi disorganization established YIF1B deficiency as a Golgipathy-ciliopathy and connected intracellular trafficking to cilia maintenance, while parallel work showed KO mice have impaired 5-HT1A autoreceptor function, reduced serotonergic innervation, and loss of SSRI responsiveness.\",\n      \"evidence\": \"Patient fibroblasts plus KO mouse cilia/brain EM and MRI (PMID:33103737); KO mouse autoradiography, behavioral assays, fluoxetine challenge (PMID:32459080)\",\n      \"pmids\": [\"33103737\", \"32459080\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Both are single studies; replication in independent cohorts needed\",\n        \"Molecular pathway from Golgi disorganization to cilia defects not delineated\",\n        \"Whether 5-HT1AR mistrafficking fully accounts for the behavioral phenotype unclear\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identifying YIF1B as the translocator that loads unglycosylated SARS-CoV-2 ORF8 into unconventional secretory vesicles revealed an unexpected role for YIF1B in unconventional protein secretion and viral pathogenesis.\",\n      \"evidence\": \"Mass spectrometry, domain interaction mapping (α4 helix/β8 sheet), KO/KD in cell and hamster models with inflammatory and survival readouts\",\n      \"pmids\": [\"39811650\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single study; mechanism of translocation across the vesicle membrane not resolved\",\n        \"Whether YIF1B mediates unconventional secretion of endogenous substrates unknown\",\n        \"Generalizability to other viral proteins not tested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A structural model of YIF1B — alone and in complex with its cargoes and scaffold partners — is needed to unify the dual cargo-recognition modes (C-tail tribasic motif vs. TMD-based) and to explain how YIF1B gates anterograde trafficking at the intermediate compartment.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No high-resolution structure of YIF1B available\",\n        \"Full repertoire of endogenous cargo beyond 5-HT1AR and TAPL unknown\",\n        \"Whether YIF1B plays a general role in unconventional secretion remains untested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [3, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [1, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 1, 2, 3]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 1, 3]}\n    ],\n    \"complexes\": [\n      \"Yif1B–Yip1A–Rab6–Kif5B vesicular trafficking complex\"\n    ],\n    \"partners\": [\n      \"YIP1A\",\n      \"RAB6\",\n      \"KIF5B\",\n      \"HTR1A\",\n      \"TAPL\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}