{"gene":"YIF1B","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2008,"finding":"YIF1B (Yif1B) interacts directly with the 5-HT1A serotonin receptor via the receptor's short C-terminal domain (17 aa region), as identified by yeast two-hybrid screen and confirmed by GST pull-down using rat brain extracts and transfected cell lines. siRNA-mediated knockdown of endogenous Yif1B in primary neuron cultures specifically prevented targeting of 5-HT1A receptor to distal portions of dendrites, without affecting other receptors (sst2A, P2X2, 5-HT3A), establishing Yif1B as a key mediator of somatodendritic targeting of the 5-HT1A receptor.","method":"Yeast two-hybrid screen, GST pull-down (rat brain extracts and transfected cells), siRNA knockdown in primary neuron cultures with receptor localization readout","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding assays (Y2H + GST pull-down) plus functional loss-of-function siRNA with specific dendritic targeting phenotype; replicated across multiple assay systems","pmids":["18685031"],"is_preprint":false},{"year":2012,"finding":"Yif1B binds directly to a tribasic motif in the C-tail of the 5-HT1A receptor with high affinity (KD ≈ 37 nM), as determined by directed mutagenesis, GST pull-down, and surface plasmon resonance. Yif1B serves as a scaffold protein recruiting a vesicular complex that includes Yip1A, Rab6, and Kif5B; knockdown of each partner in neurons impairs dendritic targeting of 5-HT1A receptor. Live videomicroscopy showed that 5-HT1A receptor, Yif1B, Yip1A, and Rab6 co-traffic in vesicles exiting the soma toward the dendritic tree with bidirectional motions.","method":"Directed mutagenesis, GST pull-down, surface plasmon resonance, siRNA knockdown in neurons, live videomicroscopy","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — SPR quantitative binding with mutagenesis identifies specific binding motif; multiple orthogonal methods; functional knockdown of each complex component","pmids":["23055492"],"is_preprint":false},{"year":2015,"finding":"Yif1B localizes to the intermediate compartment (IC) rather than as a Golgi resident, and is involved in anterograde (ER-to-Golgi) trafficking but not retrograde trafficking: depletion of Yif1B accelerated VSVG protein anterograde transport in HeLa cells and hippocampal neurons from Yif1B KO mice, whereas retrograde Shiga toxin (ShTx) traffic was unaffected. Long-term Yif1B depletion (as in KO mice) caused disorganized Golgi architecture in CA1 pyramidal neurons (confirmed by electron microscopy), but short-term depletion did not alter Golgi structure, indicating Yif1B's role in anterograde traffic is mechanistically distinct from its structural role at the Golgi.","method":"Subcellular fractionation/immunostaining for localization, VSVG trafficking assay in HeLa cells, ShTx retrograde trafficking assay, Yif1B KO mice, electron microscopy of Golgi","journal":"Traffic (Copenhagen, Denmark)","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal trafficking assays (anterograde and retrograde), KO mouse model, EM validation; negative retrograde result is informative","pmids":["26077767"],"is_preprint":false},{"year":2019,"finding":"YIF1B interacts with the lysosomal ABC transporter TAPL (ABCB9), specifically via YIF1B's transmembrane domain binding to the N-terminal transmembrane domain (TMD0) of TAPL. This interaction is strongly dependent on a salt bridge (Asp-17/Arg-57) within TMD0. YIF1B is involved in the ER-to-Golgi trafficking step of TAPL, as identified by interactome analysis and functional trafficking assays.","method":"Interactome/co-immunoprecipitation analysis, RUSH (retention using selective hooks) assay for trafficking synchronization, immunostaining, confocal microscopy, mutagenesis of charged residues in TMD0","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP interactome plus functional RUSH trafficking assay; single lab, multiple methods but interaction domain detail comes from mutagenesis in the context of TAPL rather than YIF1B","pmids":["30877195"],"is_preprint":false},{"year":2020,"finding":"Yif1B KO mice display a significant decrease in forebrain density of serotonin projection fibers and hypofunctionality of 5-HT1A autoreceptors on raphe neurons, establishing that Yif1B is required for normal serotonin neurotransmission in vivo. Yif1B KO mice showed reduced social interaction and failed to respond to the antidepressant-like effect of acute fluoxetine, demonstrating a functional link between Yif1B-mediated 5-HT1A receptor trafficking and behavioral serotonergic responses.","method":"Yif1B KO mouse model, autoradiography of 5-HT projection fiber density, electrophysiological/functional assessment of 5-HT1A autoreceptors, behavioral assays (social interaction, fluoxetine response)","journal":"Journal of psychiatry & neuroscience : JPN","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with defined neurochemical and behavioral phenotypes; single lab, multiple readouts","pmids":["32459080"],"is_preprint":false},{"year":2020,"finding":"Biallelic loss-of-function mutations in YIF1B in humans and in Yif1B KO mice cause subcellular alterations of ER and Golgi compartments in neurons. Remarkably, loss of YIF1B (which is not detected in primary cilia) causes primary cilia abnormalities in patient skin fibroblasts, Yif1B KO mouse fibroblasts, and in ciliary architectural components in the KO brain, functionally linking Golgi trafficking defects (Golgipathy) with ciliopathy.","method":"Yif1B KO mouse model, patient fibroblast analysis, immunostaining for ER/Golgi markers, electron microscopy, ciliary architecture analysis in brain","journal":"Brain : a journal of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse and patient fibroblasts provide convergent evidence; multiple subcellular readouts; single primary lab","pmids":["33103737"],"is_preprint":false},{"year":2024,"finding":"YIF1B directly translocates unglycosylated SARS-CoV-2 ORF8 protein into vesicles mediating unconventional secretion; the interaction is between the α4 helix of YIF1B and the β8 sheet of ORF8. YIF1B knockdown in cell and hamster models blocked ORF8 unconventional secretion, attenuated inflammation, and reduced mortality, establishing YIF1B as a mediator of ORF8 secretion during SARS-CoV-2 infection.","method":"Mass spectrometry interactome analysis, gene knockout/knockdown in cell lines and hamster model, domain-interaction mapping (α4 helix/β8 sheet), inflammation and mortality readouts","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-identified interaction with domain-level mapping and functional KD in two model systems (cell and in vivo hamster); single lab","pmids":["39811650"],"is_preprint":false}],"current_model":"YIF1B is an intracellular membrane-bound scaffold protein of the intermediate compartment/ER-Golgi trafficking axis that directly binds the C-terminal tribasic motif of the 5-HT1A serotonin receptor (KD ≈ 37 nM) and recruits a vesicular complex (Yip1A, Rab6, Kif5B) to drive anterograde trafficking and somatodendritic targeting of the receptor in neurons; it also participates in anterograde (but not retrograde) trafficking of other cargo including TAPL and SARS-CoV-2 ORF8 (via its α4 helix), supports Golgi architectural integrity, and is required for primary cilia organization, with loss-of-function causing serotonin neurotransmission deficits and a severe human neurodevelopmental syndrome."},"narrative":{"mechanistic_narrative":"YIF1B is an intracellular membrane scaffold of the ER-to-Golgi intermediate compartment that organizes anterograde vesicular trafficking and supports Golgi architectural integrity [PMID:26077767]. Its best-defined role is as the direct receptor for the somatodendritic targeting of the 5-HT1A serotonin receptor: it binds a tribasic motif in the receptor's C-terminal tail with high affinity (KD ≈ 37 nM) and nucleates a vesicular complex containing Yip1A, Rab6, and Kif5B that co-traffics the receptor out of the soma into the dendritic tree, with knockdown of YIF1B or any complex partner abolishing distal dendritic targeting [PMID:18685031, PMID:23055492]. YIF1B localizes to the intermediate compartment rather than as a Golgi resident and acts selectively in anterograde (ER-to-Golgi) transport while leaving retrograde traffic unaffected; its long-term loss disorganizes Golgi architecture as a mechanistically distinct consequence [PMID:26077767]. The same anterograde trafficking activity handles additional cargo: YIF1B engages the transmembrane domain of the lysosomal ABC transporter TAPL/ABCB9 at its ER-to-Golgi step [PMID:30877195] and translocates SARS-CoV-2 ORF8 into vesicles for unconventional secretion via its α4 helix [PMID:39811650]. In vivo, YIF1B loss reduces forebrain serotonergic projection density and 5-HT1A autoreceptor function with behavioral serotonergic deficits [PMID:32459080], and biallelic loss-of-function mutations cause a human neurodevelopmental syndrome featuring ER/Golgi alterations and primary cilia abnormalities, linking a Golgipathy to ciliopathy [PMID:33103737].","teleology":[{"year":2008,"claim":"Established that YIF1B is a dedicated trafficking partner of the 5-HT1A serotonin receptor, answering how this receptor reaches distal dendrites.","evidence":"Yeast two-hybrid screen plus GST pull-down from rat brain and transfected cells, with siRNA knockdown in primary neurons scoring receptor localization","pmids":["18685031"],"confidence":"High","gaps":["Binding affinity and the precise receptor motif not yet quantified","Trafficking machinery recruited by YIF1B not identified"]},{"year":2012,"claim":"Resolved the molecular basis of the interaction and defined YIF1B as a scaffold recruiting a motor/Rab vesicular complex, explaining the transport mechanism.","evidence":"Directed mutagenesis, GST pull-down, surface plasmon resonance (KD ≈ 37 nM), neuronal siRNA of each partner, and live videomicroscopy of co-trafficking vesicles","pmids":["23055492"],"confidence":"High","gaps":["Stoichiometry and assembly order of the Yip1A/Rab6/Kif5B complex unresolved","Whether YIF1B couples cargo loading to motor activation not mechanistically dissected"]},{"year":2015,"claim":"Localized YIF1B to the intermediate compartment and assigned it a directional, anterograde-specific trafficking role separable from its structural Golgi function.","evidence":"Fractionation/immunostaining, VSVG anterograde and Shiga toxin retrograde trafficking assays in HeLa cells and KO-mouse neurons, with EM of Golgi after short- versus long-term depletion","pmids":["26077767"],"confidence":"High","gaps":["Molecular basis for the acceleration of VSVG transport upon depletion unexplained","How chronic loss leads to Golgi disorganization not defined"]},{"year":2019,"claim":"Generalized YIF1B beyond serotonin receptors by showing it handles the ER-to-Golgi step of the lysosomal transporter TAPL through transmembrane-domain contacts.","evidence":"Co-IP/interactome, RUSH trafficking synchronization, confocal imaging, and TMD0 charged-residue mutagenesis","pmids":["30877195"],"confidence":"Medium","gaps":["Interaction-domain detail derives from TAPL mutagenesis rather than YIF1B residues","Single-lab evidence without reciprocal structural validation"]},{"year":2020,"claim":"Connected YIF1B trafficking function to organismal serotonergic physiology and behavior, establishing in vivo relevance.","evidence":"Yif1B KO mice with autoradiographic projection-fiber density, electrophysiology of 5-HT1A autoreceptors, and social-interaction/fluoxetine behavioral assays","pmids":["32459080"],"confidence":"Medium","gaps":["Causal chain from receptor mistargeting to fiber-density loss not fully traced","Single-lab behavioral phenotyping"]},{"year":2020,"claim":"Defined YIF1B as a disease gene whose loss couples ER/Golgi trafficking defects to ciliary abnormalities, broadening its cellular role.","evidence":"Biallelic LOF mutations in patients, KO mice and patient fibroblasts analyzed by ER/Golgi immunostaining, EM, and ciliary architecture","pmids":["33103737"],"confidence":"Medium","gaps":["Mechanistic link between Golgi trafficking and ciliogenesis not established","YIF1B is absent from cilia, so the effect is indirect by an undefined route"]},{"year":2024,"claim":"Showed YIF1B mediates unconventional secretion of a viral cargo, extending its anterograde role to pathogen-driven inflammation.","evidence":"Mass-spectrometry interactome, α4-helix/β8-sheet domain mapping, and knockdown in cell and hamster models with inflammation/mortality readouts","pmids":["39811650"],"confidence":"Medium","gaps":["Whether ORF8 uses the same Yip1A/Rab6/Kif5B machinery unknown","Single-lab interactome without reciprocal binding validation"]},{"year":null,"claim":"How YIF1B selects and discriminates among its diverse cargo and how its trafficking activity mechanistically controls Golgi and ciliary integrity remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of YIF1B or its cargo-binding interfaces","Unifying mechanism linking anterograde transport, Golgi maintenance, and ciliogenesis absent","Cargo selectivity rules across receptors, transporters, and viral proteins undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[1,3]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[2,5]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[2,1]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,3]}],"complexes":[],"partners":["HTR1A","YIPF5","RAB6","KIF5B","ABCB9"],"other_free_text":[]}},"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":"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":15,"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":"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":9,"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},{"pmid":"42253503","id":"PMC_42253503","title":"YIF1B Mutational Dysregulation Drives Cutaneous Melanoma Progression by Remodeling the TME.","date":"2026","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/42253503","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9800,"output_tokens":2430,"usd":0.032925,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9516,"output_tokens":2836,"usd":0.05924,"stage2_stop_reason":"end_turn"},"total_usd":0.092165,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"YIF1B (Yif1B) interacts directly with the 5-HT1A serotonin receptor via the receptor's short C-terminal domain (17 aa region), as identified by yeast two-hybrid screen and confirmed by GST pull-down using rat brain extracts and transfected cell lines. siRNA-mediated knockdown of endogenous Yif1B in primary neuron cultures specifically prevented targeting of 5-HT1A receptor to distal portions of dendrites, without affecting other receptors (sst2A, P2X2, 5-HT3A), establishing Yif1B as a key mediator of somatodendritic targeting of the 5-HT1A receptor.\",\n      \"method\": \"Yeast two-hybrid screen, GST pull-down (rat brain extracts and transfected cells), siRNA knockdown in primary neuron cultures with receptor localization readout\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding assays (Y2H + GST pull-down) plus functional loss-of-function siRNA with specific dendritic targeting phenotype; replicated across multiple assay 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 the 5-HT1A receptor with high affinity (KD ≈ 37 nM), as determined by directed mutagenesis, GST pull-down, and surface plasmon resonance. Yif1B serves as a scaffold protein recruiting a vesicular complex that includes Yip1A, Rab6, and Kif5B; knockdown of each partner in neurons impairs dendritic targeting of 5-HT1A receptor. Live videomicroscopy showed that 5-HT1A receptor, Yif1B, Yip1A, and Rab6 co-traffic in vesicles exiting the soma toward the dendritic tree with bidirectional motions.\",\n      \"method\": \"Directed mutagenesis, GST pull-down, surface plasmon resonance, siRNA knockdown in neurons, live videomicroscopy\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — SPR quantitative binding with mutagenesis identifies specific binding motif; multiple orthogonal methods; functional knockdown of each complex component\",\n      \"pmids\": [\"23055492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Yif1B localizes to the intermediate compartment (IC) rather than as a Golgi resident, and is involved in anterograde (ER-to-Golgi) trafficking but not retrograde trafficking: depletion of Yif1B accelerated VSVG protein anterograde transport in HeLa cells and hippocampal neurons from Yif1B KO mice, whereas retrograde Shiga toxin (ShTx) traffic was unaffected. Long-term Yif1B depletion (as in KO mice) caused disorganized Golgi architecture in CA1 pyramidal neurons (confirmed by electron microscopy), but short-term depletion did not alter Golgi structure, indicating Yif1B's role in anterograde traffic is mechanistically distinct from its structural role at the Golgi.\",\n      \"method\": \"Subcellular fractionation/immunostaining for localization, VSVG trafficking assay in HeLa cells, ShTx retrograde trafficking assay, Yif1B KO mice, electron microscopy of Golgi\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal trafficking assays (anterograde and retrograde), KO mouse model, EM validation; negative retrograde result is informative\",\n      \"pmids\": [\"26077767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"YIF1B interacts with the lysosomal ABC transporter TAPL (ABCB9), specifically via YIF1B's transmembrane domain binding to the N-terminal transmembrane domain (TMD0) of TAPL. This interaction is strongly dependent on a salt bridge (Asp-17/Arg-57) within TMD0. YIF1B is involved in the ER-to-Golgi trafficking step of TAPL, as identified by interactome analysis and functional trafficking assays.\",\n      \"method\": \"Interactome/co-immunoprecipitation analysis, RUSH (retention using selective hooks) assay for trafficking synchronization, immunostaining, confocal microscopy, mutagenesis of charged residues in TMD0\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP interactome plus functional RUSH trafficking assay; single lab, multiple methods but interaction domain detail comes from mutagenesis in the context of TAPL rather than YIF1B\",\n      \"pmids\": [\"30877195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Yif1B KO mice display a significant decrease in forebrain density of serotonin projection fibers and hypofunctionality of 5-HT1A autoreceptors on raphe neurons, establishing that Yif1B is required for normal serotonin neurotransmission in vivo. Yif1B KO mice showed reduced social interaction and failed to respond to the antidepressant-like effect of acute fluoxetine, demonstrating a functional link between Yif1B-mediated 5-HT1A receptor trafficking and behavioral serotonergic responses.\",\n      \"method\": \"Yif1B KO mouse model, autoradiography of 5-HT projection fiber density, electrophysiological/functional assessment of 5-HT1A autoreceptors, behavioral assays (social interaction, fluoxetine response)\",\n      \"journal\": \"Journal of psychiatry & neuroscience : JPN\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with defined neurochemical and behavioral phenotypes; single lab, multiple readouts\",\n      \"pmids\": [\"32459080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Biallelic loss-of-function mutations in YIF1B in humans and in Yif1B KO mice cause subcellular alterations of ER and Golgi compartments in neurons. Remarkably, loss of YIF1B (which is not detected in primary cilia) causes primary cilia abnormalities in patient skin fibroblasts, Yif1B KO mouse fibroblasts, and in ciliary architectural components in the KO brain, functionally linking Golgi trafficking defects (Golgipathy) with ciliopathy.\",\n      \"method\": \"Yif1B KO mouse model, patient fibroblast analysis, immunostaining for ER/Golgi markers, electron microscopy, ciliary architecture analysis in brain\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse and patient fibroblasts provide convergent evidence; multiple subcellular readouts; single primary lab\",\n      \"pmids\": [\"33103737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YIF1B directly translocates unglycosylated SARS-CoV-2 ORF8 protein into vesicles mediating unconventional secretion; the interaction is between the α4 helix of YIF1B and the β8 sheet of ORF8. YIF1B knockdown in cell and hamster models blocked ORF8 unconventional secretion, attenuated inflammation, and reduced mortality, establishing YIF1B as a mediator of ORF8 secretion during SARS-CoV-2 infection.\",\n      \"method\": \"Mass spectrometry interactome analysis, gene knockout/knockdown in cell lines and hamster model, domain-interaction mapping (α4 helix/β8 sheet), inflammation and mortality readouts\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-identified interaction with domain-level mapping and functional KD in two model systems (cell and in vivo hamster); single lab\",\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 trafficking axis that directly binds the C-terminal tribasic motif of the 5-HT1A serotonin receptor (KD ≈ 37 nM) and recruits a vesicular complex (Yip1A, Rab6, Kif5B) to drive anterograde trafficking and somatodendritic targeting of the receptor in neurons; it also participates in anterograde (but not retrograde) trafficking of other cargo including TAPL and SARS-CoV-2 ORF8 (via its α4 helix), supports Golgi architectural integrity, and is required for primary cilia organization, with loss-of-function causing serotonin neurotransmission deficits and a severe human neurodevelopmental syndrome.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"YIF1B is an intracellular membrane scaffold of the ER-to-Golgi intermediate compartment that organizes anterograde vesicular trafficking and supports Golgi architectural integrity [#2]. Its best-defined role is as the direct receptor for the somatodendritic targeting of the 5-HT1A serotonin receptor: it binds a tribasic motif in the receptor's C-terminal tail with high affinity (KD ≈ 37 nM) and nucleates a vesicular complex containing Yip1A, Rab6, and Kif5B that co-traffics the receptor out of the soma into the dendritic tree, with knockdown of YIF1B or any complex partner abolishing distal dendritic targeting [#0, #1]. YIF1B localizes to the intermediate compartment rather than as a Golgi resident and acts selectively in anterograde (ER-to-Golgi) transport while leaving retrograde traffic unaffected; its long-term loss disorganizes Golgi architecture as a mechanistically distinct consequence [#2]. The same anterograde trafficking activity handles additional cargo: YIF1B engages the transmembrane domain of the lysosomal ABC transporter TAPL/ABCB9 at its ER-to-Golgi step [#3] and translocates SARS-CoV-2 ORF8 into vesicles for unconventional secretion via its α4 helix [#6]. In vivo, YIF1B loss reduces forebrain serotonergic projection density and 5-HT1A autoreceptor function with behavioral serotonergic deficits [#4], and biallelic loss-of-function mutations cause a human neurodevelopmental syndrome featuring ER/Golgi alterations and primary cilia abnormalities, linking a Golgipathy to ciliopathy [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established that YIF1B is a dedicated trafficking partner of the 5-HT1A serotonin receptor, answering how this receptor reaches distal dendrites.\",\n      \"evidence\": \"Yeast two-hybrid screen plus GST pull-down from rat brain and transfected cells, with siRNA knockdown in primary neurons scoring receptor localization\",\n      \"pmids\": [\"18685031\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding affinity and the precise receptor motif not yet quantified\", \"Trafficking machinery recruited by YIF1B not identified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Resolved the molecular basis of the interaction and defined YIF1B as a scaffold recruiting a motor/Rab vesicular complex, explaining the transport mechanism.\",\n      \"evidence\": \"Directed mutagenesis, GST pull-down, surface plasmon resonance (KD ≈ 37 nM), neuronal siRNA of each partner, and live videomicroscopy of co-trafficking vesicles\",\n      \"pmids\": [\"23055492\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and assembly order of the Yip1A/Rab6/Kif5B complex unresolved\", \"Whether YIF1B couples cargo loading to motor activation not mechanistically dissected\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Localized YIF1B to the intermediate compartment and assigned it a directional, anterograde-specific trafficking role separable from its structural Golgi function.\",\n      \"evidence\": \"Fractionation/immunostaining, VSVG anterograde and Shiga toxin retrograde trafficking assays in HeLa cells and KO-mouse neurons, with EM of Golgi after short- versus long-term depletion\",\n      \"pmids\": [\"26077767\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis for the acceleration of VSVG transport upon depletion unexplained\", \"How chronic loss leads to Golgi disorganization not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Generalized YIF1B beyond serotonin receptors by showing it handles the ER-to-Golgi step of the lysosomal transporter TAPL through transmembrane-domain contacts.\",\n      \"evidence\": \"Co-IP/interactome, RUSH trafficking synchronization, confocal imaging, and TMD0 charged-residue mutagenesis\",\n      \"pmids\": [\"30877195\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interaction-domain detail derives from TAPL mutagenesis rather than YIF1B residues\", \"Single-lab evidence without reciprocal structural validation\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected YIF1B trafficking function to organismal serotonergic physiology and behavior, establishing in vivo relevance.\",\n      \"evidence\": \"Yif1B KO mice with autoradiographic projection-fiber density, electrophysiology of 5-HT1A autoreceptors, and social-interaction/fluoxetine behavioral assays\",\n      \"pmids\": [\"32459080\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal chain from receptor mistargeting to fiber-density loss not fully traced\", \"Single-lab behavioral phenotyping\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined YIF1B as a disease gene whose loss couples ER/Golgi trafficking defects to ciliary abnormalities, broadening its cellular role.\",\n      \"evidence\": \"Biallelic LOF mutations in patients, KO mice and patient fibroblasts analyzed by ER/Golgi immunostaining, EM, and ciliary architecture\",\n      \"pmids\": [\"33103737\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between Golgi trafficking and ciliogenesis not established\", \"YIF1B is absent from cilia, so the effect is indirect by an undefined route\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed YIF1B mediates unconventional secretion of a viral cargo, extending its anterograde role to pathogen-driven inflammation.\",\n      \"evidence\": \"Mass-spectrometry interactome, α4-helix/β8-sheet domain mapping, and knockdown in cell and hamster models with inflammation/mortality readouts\",\n      \"pmids\": [\"39811650\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ORF8 uses the same Yip1A/Rab6/Kif5B machinery unknown\", \"Single-lab interactome without reciprocal binding validation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How YIF1B selects and discriminates among its diverse cargo and how its trafficking activity mechanistically controls Golgi and ciliary integrity remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of YIF1B or its cargo-binding interfaces\", \"Unifying mechanism linking anterograde transport, Golgi maintenance, and ciliogenesis absent\", \"Cargo selectivity rules across receptors, transporters, and viral proteins undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005793\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [2, 5]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [2, 1]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"HTR1A\", \"YIPF5\", \"RAB6\", \"KIF5B\", \"ABCB9\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}