{"gene":"TMEM268","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2018,"finding":"TMEM268 interacts with integrin subunit β4 (ITGB4) via a C-terminal interaction; TMEM268 knockout promotes ITGB4 ubiquitin-mediated degradation, increasing instability of ITGB4 and filamin A (FLNA), leading to disassociation of the ITGB4/PLEC complex and disrupted cytoskeleton remodeling.","method":"Co-immunoprecipitation (C-terminal interaction mapping), TMEM268 knockout cell lines (BGC823), xenograft mouse model, cell viability/proliferation/adhesion assays, ubiquitination assays","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP identifying binding domain, KO cell lines with multiple orthogonal phenotypic readouts (proliferation, adhesion, cytoskeleton, in vivo tumorigenesis), and mechanistic follow-up on ubiquitin-mediated degradation","pmids":["30361615"],"is_preprint":false},{"year":2024,"finding":"TMEM268 interacts with CD11b (integrin subunit αM) and inhibits its degradation via the endosome-lysosome pathway; Tmem268 knockout in mice impairs phagocyte adhesion and migration, decreases phagocyte infiltration at infection sites, and reduces complement-dependent phagocytosis, thereby aggravating cecal ligation and puncture-induced sepsis.","method":"Co-immunoprecipitation (TMEM268–CD11b interaction), Tmem268 knockout mice, cecal ligation and puncture sepsis model, phagocyte adhesion/migration assays, endosome-lysosome pathway inhibition experiments","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying binding partner, KO mouse model with multiple orthogonal functional readouts (bacterial burden, phagocyte infiltration, complement-dependent phagocytosis), and mechanistic pathway placement (endosome-lysosome degradation)","pmids":["38730209"],"is_preprint":false}],"current_model":"TMEM268 is a transmembrane protein that stabilizes integrin subunits (ITGB4 and CD11b) by binding them and preventing their ubiquitin- or endosome-lysosome-mediated degradation, thereby positively regulating ITGB4/PLEC cytoskeletal signaling in epithelial/cancer cells and β2 integrin-dependent phagocyte adhesion, migration, and anti-infectious immune responses in vivo."},"narrative":{"mechanistic_narrative":"TMEM268 is a transmembrane protein that functions as a stabilizer of integrin subunits, preventing their degradation and thereby supporting integrin-dependent cytoskeletal signaling and phagocyte function [PMID:30361615, PMID:38730209]. In epithelial/cancer cells, TMEM268 binds integrin β4 (ITGB4) through a C-terminal interaction and protects it from ubiquitin-mediated degradation; loss of TMEM268 destabilizes ITGB4 and filamin A, dissociates the ITGB4/PLEC complex, and disrupts cytoskeleton remodeling, with consequences for proliferation, adhesion, and tumorigenesis [PMID:30361615]. In phagocytes, TMEM268 binds the β2 integrin subunit CD11b (integrin αM) and inhibits its endosome-lysosome-mediated degradation, and its loss impairs phagocyte adhesion, migration, and complement-dependent phagocytosis, worsening sepsis in vivo [PMID:38730209]. Beyond these two integrin-stabilizing roles, no further mechanistic detail has been characterized in the available corpus.","teleology":[{"year":2018,"claim":"Established the first molecular function for TMEM268 by showing it binds and stabilizes the integrin subunit ITGB4, linking it to cytoskeletal signaling and tumor biology.","evidence":"Reciprocal Co-IP with C-terminal interaction mapping, TMEM268 knockout cell lines, ubiquitination assays, and xenograft tumor models","pmids":["30361615"],"confidence":"High","gaps":["Identity of the E3 ligase mediating ITGB4 ubiquitination not defined","No structural model of the TMEM268 C-terminus-ITGB4 interface","Membrane topology and subcellular site of the stabilization event not resolved"]},{"year":2024,"claim":"Extended TMEM268 function to immune cells, showing it stabilizes the β2 integrin subunit CD11b by blocking endosome-lysosome degradation and is required for phagocyte-mediated anti-infectious responses.","evidence":"Co-IP for the TMEM268-CD11b interaction, Tmem268 knockout mice, cecal ligation and puncture sepsis model, and phagocyte adhesion/migration and complement-dependent phagocytosis assays","pmids":["38730209"],"confidence":"High","gaps":["Whether ITGB4 and CD11b stabilization share a common molecular mechanism not addressed","The degradation machinery (specific endosomal/lysosomal route) directing CD11b not detailed","Direct versus indirect nature of the TMEM268-CD11b binding not fully dissected"]},{"year":null,"claim":"Whether TMEM268 acts as a general integrin chaperone/stabilizer across additional integrin subunits, and the precise biochemical mechanism by which it shields partners from degradation, remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No defined enzymatic or adaptor activity for the stabilization mechanism","No structural characterization of the protein","Breadth of integrin partners beyond ITGB4 and CD11b unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1]}],"pathway":[],"complexes":[],"partners":["ITGB4","ITGAM"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q5VZI3","full_name":"Transmembrane protein 268","aliases":[],"length_aa":342,"mass_kda":37.6,"function":"Stabilizes cell surface expression of ITGAM and participates in the adhesion and migration of phagocytes during bacterial clearance","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q5VZI3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TMEM268","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TMEM268","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TMEM268"},"hgnc":{"alias_symbol":["DKFZp547P234","FLJ38045"],"prev_symbol":["C9orf91"]},"alphafold":{"accession":"Q5VZI3","domains":[{"cath_id":"-","chopping":"38-200","consensus_level":"medium","plddt":75.8928,"start":38,"end":200},{"cath_id":"-","chopping":"203-235_274-335","consensus_level":"medium","plddt":80.9703,"start":203,"end":335}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5VZI3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5VZI3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5VZI3-F1-predicted_aligned_error_v6.png","plddt_mean":71.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TMEM268","jax_strain_url":"https://www.jax.org/strain/search?query=TMEM268"},"sequence":{"accession":"Q5VZI3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5VZI3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5VZI3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5VZI3"}},"corpus_meta":[{"pmid":"30361615","id":"PMC_30361615","title":"Deletion of TMEM268 inhibits growth of gastric cancer cells by downregulating the ITGB4 signaling pathway.","date":"2018","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/30361615","citation_count":29,"is_preprint":false},{"pmid":"38636565","id":"PMC_38636565","title":"Mediterranean diet protects against a neuroinflammatory cortical transcriptome: Associations with brain volumetrics, peripheral inflammation, social isolation, and anxiety in nonhuman primates (Macaca fascicularis).","date":"2024","source":"Brain, behavior, and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/38636565","citation_count":23,"is_preprint":false},{"pmid":"21480186","id":"PMC_21480186","title":"Systematic candidate gene investigations in the SPA2 locus (9q32) show an association between TNFSF8 and susceptibility to spondylarthritis.","date":"2011","source":"Arthritis and rheumatism","url":"https://pubmed.ncbi.nlm.nih.gov/21480186","citation_count":8,"is_preprint":false},{"pmid":"37961556","id":"PMC_37961556","title":"Mediterranean Diet Protects Against a Neuroinflammatory Cortical Transcriptome: Associations with Brain Volumetrics, Peripheral Inflammation, Social Isolation and Anxiety.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/37961556","citation_count":1,"is_preprint":false},{"pmid":"38730209","id":"PMC_38730209","title":"Deletion of Tmem268 in mice suppresses anti-infectious immune responses by downregulating CD11b signaling.","date":"2024","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/38730209","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":5130,"output_tokens":729,"usd":0.013163,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7143,"output_tokens":1371,"usd":0.034995,"stage2_stop_reason":"end_turn"},"total_usd":0.048158,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2018,\n      \"finding\": \"TMEM268 interacts with integrin subunit β4 (ITGB4) via a C-terminal interaction; TMEM268 knockout promotes ITGB4 ubiquitin-mediated degradation, increasing instability of ITGB4 and filamin A (FLNA), leading to disassociation of the ITGB4/PLEC complex and disrupted cytoskeleton remodeling.\",\n      \"method\": \"Co-immunoprecipitation (C-terminal interaction mapping), TMEM268 knockout cell lines (BGC823), xenograft mouse model, cell viability/proliferation/adhesion assays, ubiquitination assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP identifying binding domain, KO cell lines with multiple orthogonal phenotypic readouts (proliferation, adhesion, cytoskeleton, in vivo tumorigenesis), and mechanistic follow-up on ubiquitin-mediated degradation\",\n      \"pmids\": [\"30361615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TMEM268 interacts with CD11b (integrin subunit αM) and inhibits its degradation via the endosome-lysosome pathway; Tmem268 knockout in mice impairs phagocyte adhesion and migration, decreases phagocyte infiltration at infection sites, and reduces complement-dependent phagocytosis, thereby aggravating cecal ligation and puncture-induced sepsis.\",\n      \"method\": \"Co-immunoprecipitation (TMEM268–CD11b interaction), Tmem268 knockout mice, cecal ligation and puncture sepsis model, phagocyte adhesion/migration assays, endosome-lysosome pathway inhibition experiments\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying binding partner, KO mouse model with multiple orthogonal functional readouts (bacterial burden, phagocyte infiltration, complement-dependent phagocytosis), and mechanistic pathway placement (endosome-lysosome degradation)\",\n      \"pmids\": [\"38730209\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TMEM268 is a transmembrane protein that stabilizes integrin subunits (ITGB4 and CD11b) by binding them and preventing their ubiquitin- or endosome-lysosome-mediated degradation, thereby positively regulating ITGB4/PLEC cytoskeletal signaling in epithelial/cancer cells and β2 integrin-dependent phagocyte adhesion, migration, and anti-infectious immune responses in vivo.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TMEM268 is a transmembrane protein that functions as a stabilizer of integrin subunits, preventing their degradation and thereby supporting integrin-dependent cytoskeletal signaling and phagocyte function [#0, #1]. In epithelial/cancer cells, TMEM268 binds integrin β4 (ITGB4) through a C-terminal interaction and protects it from ubiquitin-mediated degradation; loss of TMEM268 destabilizes ITGB4 and filamin A, dissociates the ITGB4/PLEC complex, and disrupts cytoskeleton remodeling, with consequences for proliferation, adhesion, and tumorigenesis [#0]. In phagocytes, TMEM268 binds the β2 integrin subunit CD11b (integrin αM) and inhibits its endosome-lysosome-mediated degradation, and its loss impairs phagocyte adhesion, migration, and complement-dependent phagocytosis, worsening sepsis in vivo [#1]. Beyond these two integrin-stabilizing roles, no further mechanistic detail has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2018,\n      \"claim\": \"Established the first molecular function for TMEM268 by showing it binds and stabilizes the integrin subunit ITGB4, linking it to cytoskeletal signaling and tumor biology.\",\n      \"evidence\": \"Reciprocal Co-IP with C-terminal interaction mapping, TMEM268 knockout cell lines, ubiquitination assays, and xenograft tumor models\",\n      \"pmids\": [\"30361615\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Identity of the E3 ligase mediating ITGB4 ubiquitination not defined\",\n        \"No structural model of the TMEM268 C-terminus-ITGB4 interface\",\n        \"Membrane topology and subcellular site of the stabilization event not resolved\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended TMEM268 function to immune cells, showing it stabilizes the β2 integrin subunit CD11b by blocking endosome-lysosome degradation and is required for phagocyte-mediated anti-infectious responses.\",\n      \"evidence\": \"Co-IP for the TMEM268-CD11b interaction, Tmem268 knockout mice, cecal ligation and puncture sepsis model, and phagocyte adhesion/migration and complement-dependent phagocytosis assays\",\n      \"pmids\": [\"38730209\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether ITGB4 and CD11b stabilization share a common molecular mechanism not addressed\",\n        \"The degradation machinery (specific endosomal/lysosomal route) directing CD11b not detailed\",\n        \"Direct versus indirect nature of the TMEM268-CD11b binding not fully dissected\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether TMEM268 acts as a general integrin chaperone/stabilizer across additional integrin subunits, and the precise biochemical mechanism by which it shields partners from degradation, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No defined enzymatic or adaptor activity for the stabilization mechanism\",\n        \"No structural characterization of the protein\",\n        \"Breadth of integrin partners beyond ITGB4 and CD11b unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [\"ITGB4\", \"ITGAM\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":2,"faith_total":3,"faith_pct":66.66666666666667}}