{"gene":"YIPF2","run_date":"2026-04-28T23:00:23","timeline":{"discoveries":[{"year":2019,"finding":"YIPF2 was identified as an ER-Golgi-resident transmembrane protein that acts as a Rab-GDF (GDI-displacement factor), recruiting and activating Rab5 and Rab22a GTPases to endomembrane structures, thereby regulating CD147 endocytic recycling and glycosylation in HCC cells.","method":"MAPPIT protein-protein interaction screen, GST-RBD pulldown for Rab GTPase activation, confocal imaging, flow cytometry, biotin-labeled chase assays, gelatin zymography","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (interaction trap, Rab activation pulldown, trafficking assays) in a single study with functional readouts","pmids":["31189879"],"is_preprint":false},{"year":2016,"finding":"YIPF2 primarily localizes to the trans-Golgi, has a topology with a long cytosol-facing N-terminal region followed by 5 transmembrane domains and a lumenal C-terminus, and its depletion causes specific morphological changes to the Golgi complex.","method":"Immunofluorescence microscopy, RNA interference, membrane topology assays","journal":"Histochemistry and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization and topology experiments with functional (morphological) consequence, single lab","pmids":["27999994"],"is_preprint":false},{"year":2017,"finding":"YIPF2 localizes to medial-/trans-Golgi and TGN, forms a stable complex with YIPF6, and knockdown of YIPF2 markedly delays Golgi reassembly after brefeldin A washout and reduces intracellular glycan levels in HT-29 cells.","method":"Immunofluorescence staining, brefeldin A treatment/washout, RNA interference (knockdown), glycan detection assays","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 2 — reciprocal complex formation with YIPF6 confirmed, multiple functional readouts (Golgi reassembly, glycan synthesis), replicates localization finding from independent lab","pmids":["28286305"],"is_preprint":false},{"year":2020,"finding":"YIPF2 physically interacts with TNFRSF10B (TRAIL-R2/DR5) and RAB8, inhibits the RAB8-mediated removal of TNFRSF10B from the plasma membrane, and thereby promotes TNFRSF10B recycling to the cell surface and enhances chemotherapy-induced apoptosis in NSCLC cells.","method":"Co-immunoprecipitation, flow cytometry (surface receptor level), siRNA knockdown, cell viability/apoptosis assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 — reciprocal Co-IP plus functional surface recycling assay, single lab","pmids":["32303681"],"is_preprint":false},{"year":2024,"finding":"YIPF2 depletion impairs homologous recombination (HR) DNA repair, triggers DNA damage response, and leads to cellular senescence; overexpression of YIPF2 facilitates cellular recovery from chemotherapy-induced or replicative senescence-associated DNA damage, indicating a role for Golgi-resident YIPF2 in maintaining genome integrity.","method":"Whole-genome RNAi screen, HR repair assays, DNA damage response markers, senescence assays, overexpression rescue experiments","journal":"Cell & bioscience","confidence":"Medium","confidence_rationale":"Tier 2 — genome-wide screen followed by functional validation with loss- and gain-of-function, single lab","pmids":["39238039"],"is_preprint":false},{"year":2024,"finding":"YIPF2 modulates CD147 translocation to the cell membrane in oligodendrocytes; YIPF2 inhibition increases CD147 surface levels, optimizes MCT1-CD147 binding, and ameliorates hIAPP-induced acidosis and demyelination in a diabetic encephalopathy model.","method":"Western blotting, co-immunoprecipitation, proteomic differential analysis, YIPF2 inhibition in vitro and in vivo (DE model mice)","journal":"Neuroscience bulletin","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP and proteomic identification plus in vivo functional rescue, single lab","pmids":["39078594"],"is_preprint":false}],"current_model":"YIPF2 is a multi-pass transmembrane protein resident in the medial-/trans-Golgi that acts as a Rab-GDF, recruiting and activating Rab5 and Rab22a to regulate endocytic recycling and ER-Golgi trafficking of cargo proteins (including CD147 and TNFRSF10B), supports Golgi reassembly and glycan synthesis through a complex with YIPF6, and additionally maintains genome integrity by facilitating homologous recombination DNA repair."},"narrative":{"teleology":[{"year":2016,"claim":"Establishing where YIPF2 resides and how it is oriented: topology and localization experiments placed YIPF2 at the trans-Golgi with five transmembrane domains and a cytosol-facing N-terminus, and showed that its depletion alters Golgi morphology, implicating it in Golgi structure maintenance.","evidence":"Immunofluorescence, RNA interference, and membrane topology assays in cultured cells","pmids":["27999994"],"confidence":"Medium","gaps":["Topology determined by a single lab; independent confirmation with protease protection or glycosylation mapping not reported","Mechanism by which YIPF2 depletion disrupts Golgi morphology not defined","No interacting partners identified at this stage"]},{"year":2017,"claim":"Demonstrating that YIPF2 forms a functional complex with YIPF6 and is required for Golgi reassembly and glycan biosynthesis resolved the question of how Yip-family proteins cooperate at the Golgi and linked YIPF2 to post-mitotic Golgi reformation.","evidence":"Reciprocal immunoprecipitation for YIPF2–YIPF6 complex, brefeldin A washout Golgi reassembly kinetics, glycan detection assays, and RNAi in HT-29 cells","pmids":["28286305"],"confidence":"High","gaps":["Stoichiometry and direct versus indirect nature of the YIPF2–YIPF6 interaction not resolved","Whether glycan reduction is a direct biosynthetic defect or secondary to Golgi disorganization is unclear"]},{"year":2019,"claim":"Identifying YIPF2 as a Rab-GDF that activates Rab5 and Rab22a answered the long-standing question of how Rab GTPases are recruited to ER-Golgi membranes, and connected this activity to CD147 endocytic recycling and glycosylation in hepatocellular carcinoma cells.","evidence":"MAPPIT interaction screen, GST-RBD pulldown for activated Rab, confocal colocalization, biotin-chase recycling assays, gelatin zymography in HCC cells","pmids":["31189879"],"confidence":"High","gaps":["Structural basis of GDF activity not determined","Whether YIPF2 acts on additional Rab family members beyond Rab5 and Rab22a is untested","In vivo relevance of CD147 recycling regulation not shown"]},{"year":2020,"claim":"Showing that YIPF2 physically interacts with TNFRSF10B and RAB8 and opposes RAB8-mediated receptor internalization established YIPF2 as a regulator of death receptor surface availability and chemotherapy-induced apoptosis.","evidence":"Co-immunoprecipitation, siRNA knockdown, flow cytometry for surface TNFRSF10B, and apoptosis assays in NSCLC cells","pmids":["32303681"],"confidence":"Medium","gaps":["Single-lab co-IP; reciprocal endogenous validation limited","Whether YIPF2 directly competes with RAB8 for TNFRSF10B binding or acts indirectly is unresolved","Generalizability of this mechanism to other death receptors not tested"]},{"year":2024,"claim":"Discovery that YIPF2 depletion impairs homologous recombination DNA repair and induces senescence, while its overexpression rescues DNA damage, unexpectedly extended YIPF2 function beyond membrane trafficking to genome maintenance.","evidence":"Whole-genome RNAi screen, HR repair reporter assays, DNA damage response markers, senescence assays, and overexpression rescue experiments","pmids":["39238039"],"confidence":"Medium","gaps":["Mechanistic link between Golgi-resident YIPF2 and nuclear HR repair machinery is unknown","Whether YIPF2 translocates to the nucleus or acts indirectly through signaling has not been tested","Single-lab finding not yet independently replicated"]},{"year":2024,"claim":"Demonstration that YIPF2 inhibition increases CD147 surface levels in oligodendrocytes and rescues demyelination in a diabetic encephalopathy model extended the CD147-trafficking function to a disease-relevant neural context.","evidence":"Western blot, co-immunoprecipitation, proteomics, and in vivo YIPF2 inhibition in diabetic encephalopathy model mice","pmids":["39078594"],"confidence":"Medium","gaps":["Pharmacological tool for YIPF2 inhibition not well characterized; off-target effects possible","Direction of YIPF2 effect on CD147 surface levels appears opposite to HCC findings, mechanistic reconciliation absent","Long-term consequences of YIPF2 inhibition in vivo not assessed"]},{"year":null,"claim":"The structural basis of YIPF2's Rab-GDF activity and the mechanism linking this Golgi-resident protein to nuclear homologous recombination remain major open questions.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure of YIPF2 or YIPF2–Rab complex exists","Whether YIPF2 has a nuclear pool or acts on HR indirectly via signaling is unknown","Context-dependent directionality of YIPF2 effects on CD147 trafficking (retention vs. recycling) has not been mechanistically explained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,3]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[0,1,2]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,2,3]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[4]}],"complexes":["YIPF2–YIPF6 complex"],"partners":["YIPF6","RAB5A","RAB22A","RAB8A","BSG","TNFRSF10B"],"other_free_text":[]},"mechanistic_narrative":"YIPF2 is a multi-pass transmembrane protein of the medial-/trans-Golgi network that functions as a Rab GDI-displacement factor (GDF) and cargo trafficking regulator, linking Golgi membrane dynamics to endocytic recycling, glycosylation, and genome integrity. YIPF2 recruits and activates Rab5 and Rab22a on endomembranes to control endocytic recycling of cargo proteins such as CD147 and TNFRSF10B, and physically interacts with RAB8 to inhibit RAB8-mediated internalization of TNFRSF10B, thereby sustaining its surface levels and enhancing TRAIL-dependent apoptosis [PMID:31189879, PMID:32303681]. It forms a stable complex with YIPF6 and is required for Golgi reassembly after brefeldin A treatment and for intracellular glycan synthesis [PMID:28286305]. YIPF2 depletion also impairs homologous recombination DNA repair and triggers cellular senescence, revealing an unexpected role for this Golgi-resident protein in maintaining genome integrity [PMID:39238039]."},"prefetch_data":{"uniprot":{"accession":"Q9BWQ6","full_name":"Protein YIPF2","aliases":["YIP1 family member 2"],"length_aa":316,"mass_kda":35.2,"function":"","subcellular_location":"Golgi apparatus, cis-Golgi network membrane; Golgi apparatus, trans-Golgi network membrane; Late endosome membrane","url":"https://www.uniprot.org/uniprotkb/Q9BWQ6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/YIPF2","classification":"Not Classified","n_dependent_lines":35,"n_total_lines":1208,"dependency_fraction":0.028973509933774833},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/YIPF2","total_profiled":1310},"omim":[{"mim_id":"617522","title":"YIP1 DOMAIN FAMILY, MEMBER 2; YIPF2","url":"https://www.omim.org/entry/617522"},{"mim_id":"617521","title":"YIP1 DOMAIN FAMILY, MEMBER 1; YIPF1","url":"https://www.omim.org/entry/617521"},{"mim_id":"300996","title":"YIP1 DOMAIN FAMILY, MEMBER 6; YIPF6","url":"https://www.omim.org/entry/300996"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Mitochondria","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/YIPF2"},"hgnc":{"alias_symbol":["MGC3262","FinGER2","Yip5C","YIPFbeta3B"],"prev_symbol":[]},"alphafold":{"accession":"Q9BWQ6","domains":[{"cath_id":"-","chopping":"90-281","consensus_level":"high","plddt":88.2709,"start":90,"end":281}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BWQ6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BWQ6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BWQ6-F1-predicted_aligned_error_v6.png","plddt_mean":75.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=YIPF2","jax_strain_url":"https://www.jax.org/strain/search?query=YIPF2"},"sequence":{"accession":"Q9BWQ6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BWQ6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BWQ6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BWQ6"}},"corpus_meta":[{"pmid":"21670465","id":"PMC_21670465","title":"Mutations in 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overexpression of YIPF2 facilitates cellular recovery from chemotherapy-induced or replicative senescence-associated DNA damage, indicating a role for Golgi-resident YIPF2 in maintaining genome integrity.\",\n      \"method\": \"Whole-genome RNAi screen, HR repair assays, DNA damage response markers, senescence assays, overexpression rescue experiments\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide screen followed by functional validation with loss- and gain-of-function, single lab\",\n      \"pmids\": [\"39238039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YIPF2 modulates CD147 translocation to the cell membrane in oligodendrocytes; YIPF2 inhibition increases CD147 surface levels, optimizes MCT1-CD147 binding, and ameliorates hIAPP-induced acidosis and demyelination in a diabetic encephalopathy model.\",\n      \"method\": \"Western blotting, co-immunoprecipitation, proteomic differential analysis, YIPF2 inhibition in vitro and in vivo (DE model mice)\",\n      \"journal\": \"Neuroscience bulletin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP and proteomic identification plus in vivo functional rescue, single lab\",\n      \"pmids\": [\"39078594\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"YIPF2 is a multi-pass transmembrane protein resident in the medial-/trans-Golgi that acts as a Rab-GDF, recruiting and activating Rab5 and Rab22a to regulate endocytic recycling and ER-Golgi trafficking of cargo proteins (including CD147 and TNFRSF10B), supports Golgi reassembly and glycan synthesis through a complex with YIPF6, and additionally maintains genome integrity by facilitating homologous recombination DNA repair.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"YIPF2 is a multi-pass transmembrane protein of the medial-/trans-Golgi network that functions as a Rab GDI-displacement factor (GDF) and cargo trafficking regulator, linking Golgi membrane dynamics to endocytic recycling, glycosylation, and genome integrity. YIPF2 recruits and activates Rab5 and Rab22a on endomembranes to control endocytic recycling of cargo proteins such as CD147 and TNFRSF10B, and physically interacts with RAB8 to inhibit RAB8-mediated internalization of TNFRSF10B, thereby sustaining its surface levels and enhancing TRAIL-dependent apoptosis [PMID:31189879, PMID:32303681]. It forms a stable complex with YIPF6 and is required for Golgi reassembly after brefeldin A treatment and for intracellular glycan synthesis [PMID:28286305]. YIPF2 depletion also impairs homologous recombination DNA repair and triggers cellular senescence, revealing an unexpected role for this Golgi-resident protein in maintaining genome integrity [PMID:39238039].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Establishing where YIPF2 resides and how it is oriented: topology and localization experiments placed YIPF2 at the trans-Golgi with five transmembrane domains and a cytosol-facing N-terminus, and showed that its depletion alters Golgi morphology, implicating it in Golgi structure maintenance.\",\n      \"evidence\": \"Immunofluorescence, RNA interference, and membrane topology assays in cultured cells\",\n      \"pmids\": [\"27999994\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Topology determined by a single lab; independent confirmation with protease protection or glycosylation mapping not reported\",\n        \"Mechanism by which YIPF2 depletion disrupts Golgi morphology not defined\",\n        \"No interacting partners identified at this stage\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrating that YIPF2 forms a functional complex with YIPF6 and is required for Golgi reassembly and glycan biosynthesis resolved the question of how Yip-family proteins cooperate at the Golgi and linked YIPF2 to post-mitotic Golgi reformation.\",\n      \"evidence\": \"Reciprocal immunoprecipitation for YIPF2–YIPF6 complex, brefeldin A washout Golgi reassembly kinetics, glycan detection assays, and RNAi in HT-29 cells\",\n      \"pmids\": [\"28286305\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Stoichiometry and direct versus indirect nature of the YIPF2–YIPF6 interaction not resolved\",\n        \"Whether glycan reduction is a direct biosynthetic defect or secondary to Golgi disorganization is unclear\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identifying YIPF2 as a Rab-GDF that activates Rab5 and Rab22a answered the long-standing question of how Rab GTPases are recruited to ER-Golgi membranes, and connected this activity to CD147 endocytic recycling and glycosylation in hepatocellular carcinoma cells.\",\n      \"evidence\": \"MAPPIT interaction screen, GST-RBD pulldown for activated Rab, confocal colocalization, biotin-chase recycling assays, gelatin zymography in HCC cells\",\n      \"pmids\": [\"31189879\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of GDF activity not determined\",\n        \"Whether YIPF2 acts on additional Rab family members beyond Rab5 and Rab22a is untested\",\n        \"In vivo relevance of CD147 recycling regulation not shown\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showing that YIPF2 physically interacts with TNFRSF10B and RAB8 and opposes RAB8-mediated receptor internalization established YIPF2 as a regulator of death receptor surface availability and chemotherapy-induced apoptosis.\",\n      \"evidence\": \"Co-immunoprecipitation, siRNA knockdown, flow cytometry for surface TNFRSF10B, and apoptosis assays in NSCLC cells\",\n      \"pmids\": [\"32303681\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab co-IP; reciprocal endogenous validation limited\",\n        \"Whether YIPF2 directly competes with RAB8 for TNFRSF10B binding or acts indirectly is unresolved\",\n        \"Generalizability of this mechanism to other death receptors not tested\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Discovery that YIPF2 depletion impairs homologous recombination DNA repair and induces senescence, while its overexpression rescues DNA damage, unexpectedly extended YIPF2 function beyond membrane trafficking to genome maintenance.\",\n      \"evidence\": \"Whole-genome RNAi screen, HR repair reporter assays, DNA damage response markers, senescence assays, and overexpression rescue experiments\",\n      \"pmids\": [\"39238039\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanistic link between Golgi-resident YIPF2 and nuclear HR repair machinery is unknown\",\n        \"Whether YIPF2 translocates to the nucleus or acts indirectly through signaling has not been tested\",\n        \"Single-lab finding not yet independently replicated\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstration that YIPF2 inhibition increases CD147 surface levels in oligodendrocytes and rescues demyelination in a diabetic encephalopathy model extended the CD147-trafficking function to a disease-relevant neural context.\",\n      \"evidence\": \"Western blot, co-immunoprecipitation, proteomics, and in vivo YIPF2 inhibition in diabetic encephalopathy model mice\",\n      \"pmids\": [\"39078594\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Pharmacological tool for YIPF2 inhibition not well characterized; off-target effects possible\",\n        \"Direction of YIPF2 effect on CD147 surface levels appears opposite to HCC findings, mechanistic reconciliation absent\",\n        \"Long-term consequences of YIPF2 inhibition in vivo not assessed\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of YIPF2's Rab-GDF activity and the mechanism linking this Golgi-resident protein to nuclear homologous recombination remain major open questions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No crystal or cryo-EM structure of YIPF2 or YIPF2–Rab complex exists\",\n        \"Whether YIPF2 has a nuclear pool or acts on HR indirectly via signaling is unknown\",\n        \"Context-dependent directionality of YIPF2 effects on CD147 trafficking (retention vs. recycling) has not been mechanistically explained\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [\n      \"YIPF2–YIPF6 complex\"\n    ],\n    \"partners\": [\n      \"YIPF6\",\n      \"RAB5A\",\n      \"RAB22A\",\n      \"RAB8A\",\n      \"BSG\",\n      \"TNFRSF10B\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}