{"gene":"ITPRIPL1","run_date":"2026-04-28T18:06:54","timeline":{"discoveries":[{"year":2024,"finding":"ITPRIPL1 functions as an inhibitory ligand of CD3ε on T cells; its extracellular domain binds CD3ε and significantly decreases calcium influx and ZAP70 phosphorylation, thereby impeding initial T cell activation ('signal one') and enabling tumor immune evasion.","method":"Co-immunoprecipitation/binding assays, calcium influx assays, ZAP70 phosphorylation assays, neutralizing antibody treatment in mouse tumor models","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (binding assay, functional calcium/ZAP70 readouts, in vivo mouse models, canine clinical validation) in a single rigorous study","pmids":["38614099"],"is_preprint":false},{"year":2023,"finding":"ITPRIPL1 is overexpressed in non-small cell lung cancer tissue and its expression is negatively correlated with CD8+ T cell infiltration, consistent with its role as an immune checkpoint ligand suppressing T cell activity in the tumor microenvironment.","method":"Immunohistochemistry with anti-ITPRIPL1 monoclonal antibody on NSCLC patient tissue samples; correlation analysis with anti-CD8 staining","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 3 — single-method IHC correlation study, but directly supports the mechanistic role of ITPRIPL1 as a CD3ε ligand suppressing T cell infiltration established in the Cell paper","pmids":["38188019"],"is_preprint":false}],"current_model":"ITPRIPL1 (CD3L1) functions as a cell-surface inhibitory ligand that binds CD3ε on T cells through its extracellular domain, directly suppressing the initial phase of T cell activation by reducing calcium influx and ZAP70 phosphorylation, thereby enabling tumor immune evasion; neutralizing antibodies against ITPRIPL1 restore T cell infiltration and suppress tumor growth in vivo."},"narrative":{"teleology":[{"year":2023,"claim":"Establishing that ITPRIPL1 is aberrantly expressed in human tumors and inversely associated with cytotoxic T cell presence provided the first clinical correlate suggesting an immunosuppressive role for this previously uncharacterized protein.","evidence":"Immunohistochemistry on NSCLC patient tissue with correlation to CD8+ T cell density","pmids":["38188019"],"confidence":"Medium","gaps":["Correlative IHC without functional manipulation; does not prove causality","Limited to one tumor type (NSCLC)","No mechanistic target on T cells identified"]},{"year":2024,"claim":"Identification of CD3ε as the direct binding partner of ITPRIPL1 and demonstration that this interaction suppresses proximal TCR signaling (calcium influx, ZAP70 phosphorylation) defined ITPRIPL1 as a bona fide inhibitory immune checkpoint ligand and showed that its blockade restores antitumor immunity in vivo.","evidence":"Co-immunoprecipitation/binding assays, calcium flux measurements, ZAP70 phosphorylation assays, neutralizing antibody treatment in mouse tumor models with canine clinical validation","pmids":["38614099"],"confidence":"High","gaps":["Structural basis of the ITPRIPL1–CD3ε interaction is unresolved","Whether ITPRIPL1 signals bidirectionally into the expressing cell is unknown","Relative contribution of ITPRIPL1 versus PD-L1 and other checkpoints in different tumor contexts not established"]},{"year":null,"claim":"The structural determinants of the ITPRIPL1–CD3ε interface, the breadth of tumor types dependent on this checkpoint, and whether ITPRIPL1 blockade synergizes with existing immunotherapies remain to be defined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure of the ITPRIPL1–CD3ε complex","No systematic pan-cancer functional studies","Combination therapy with anti-PD-1/PD-L1 not formally tested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0]}],"complexes":[],"partners":["CD3E"],"other_free_text":[]},"mechanistic_narrative":"ITPRIPL1 (also termed CD3L1) is a cell-surface inhibitory ligand that binds CD3ε on T cells through its extracellular domain, suppressing the initial phase of T cell activation by reducing calcium influx and ZAP70 phosphorylation [PMID:38614099]. ITPRIPL1 is overexpressed in non-small cell lung cancer, where its expression inversely correlates with CD8+ T cell infiltration, consistent with a role in tumor immune evasion [PMID:38188019]. Neutralizing antibodies against ITPRIPL1 restore T cell infiltration and suppress tumor growth in vivo, establishing it as a functional immune checkpoint [PMID:38614099]."},"prefetch_data":{"uniprot":{"accession":"Q6GPH6","full_name":"Inositol 1,4,5-trisphosphate receptor-interacting protein-like 1","aliases":[],"length_aa":555,"mass_kda":63.4,"function":"Functions as a ligand of CD3E, inhibiting TCR-CD3 complex signaling to regulate T cell activation. Induces stable CD3E-NCK1 binding, thereby preventing the CD3E-ZAP70 interaction and subsequently inhibiting the activation of the downstream ERK-NFkB signaling cascade and calcium influx","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q6GPH6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ITPRIPL1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2},{"gene":"RTN4","stoichiometry":0.2},{"gene":"STK4","stoichiometry":0.2},{"gene":"VAPA","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ITPRIPL1","total_profiled":1310},"omim":[{"mim_id":"620821","title":"ITPRIP-LIKE PROTEIN 1; ITPRIPL1","url":"https://www.omim.org/entry/620821"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"testis","ntpm":26.1}],"url":"https://www.proteinatlas.org/search/ITPRIPL1"},"hgnc":{"alias_symbol":["D1B"],"prev_symbol":["KIAA1754L"]},"alphafold":{"accession":"Q6GPH6","domains":[{"cath_id":"1.10.1410.40","chopping":"157-178_403-434_443-547","consensus_level":"medium","plddt":90.9329,"start":157,"end":547},{"cath_id":"3.30.460.90","chopping":"182-278_295-398","consensus_level":"medium","plddt":86.3233,"start":182,"end":398}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6GPH6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6GPH6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6GPH6-F1-predicted_aligned_error_v6.png","plddt_mean":78.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ITPRIPL1","jax_strain_url":"https://www.jax.org/strain/search?query=ITPRIPL1"},"sequence":{"accession":"Q6GPH6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6GPH6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6GPH6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6GPH6"}},"corpus_meta":[{"pmid":"14612495","id":"PMC_14612495","title":"An 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Theoretical and applied genetics. Theoretische und angewandte Genetik","url":"https://pubmed.ncbi.nlm.nih.gov/39141110","citation_count":2,"is_preprint":false},{"pmid":"41205820","id":"PMC_41205820","title":"Population transcriptome and phenotype analyses reveal that Rht-D1b contributed a larger seedling root to modern bread wheat.","date":"2025","source":"The Plant cell","url":"https://pubmed.ncbi.nlm.nih.gov/41205820","citation_count":1,"is_preprint":false},{"pmid":"11680625","id":"PMC_11680625","title":"Rat pancreatic acinar cells express a cytosolic phospholipase D1b isoform that is not regulated by cholecystokinin.","date":"2001","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/11680625","citation_count":1,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.22.677111","title":"A century of breeding has preserved genetic variation, accumulated favorable alleles, and shaped the <i>Rht</i> genes portfolio in North American spring wheat","date":"2025-09-23","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.22.677111","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.04.17.649374","title":"INDETERMINATE DOMAIN-DELLA protein interactions orchestrate gibberellin-mediated cell elongation in wheat and barley","date":"2025-04-18","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.17.649374","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.08.05.606718","title":"Manipulation of the microRNA172 -<i>AP2L2</i>interaction provides precise control of wheat and triticale plant height","date":"2024-08-07","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.05.606718","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":30602,"output_tokens":588,"usd":0.050313},"stage2":{"model":"claude-opus-4-6","input_tokens":3769,"output_tokens":2052,"usd":0.105218},"total_usd":0.155531,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2024,\n      \"finding\": \"ITPRIPL1 functions as an inhibitory ligand of CD3ε on T cells; its extracellular domain binds CD3ε and significantly decreases calcium influx and ZAP70 phosphorylation, thereby impeding initial T cell activation ('signal one') and enabling tumor immune evasion.\",\n      \"method\": \"Co-immunoprecipitation/binding assays, calcium influx assays, ZAP70 phosphorylation assays, neutralizing antibody treatment in mouse tumor models\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (binding assay, functional calcium/ZAP70 readouts, in vivo mouse models, canine clinical validation) in a single rigorous study\",\n      \"pmids\": [\"38614099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ITPRIPL1 is overexpressed in non-small cell lung cancer tissue and its expression is negatively correlated with CD8+ T cell infiltration, consistent with its role as an immune checkpoint ligand suppressing T cell activity in the tumor microenvironment.\",\n      \"method\": \"Immunohistochemistry with anti-ITPRIPL1 monoclonal antibody on NSCLC patient tissue samples; correlation analysis with anti-CD8 staining\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single-method IHC correlation study, but directly supports the mechanistic role of ITPRIPL1 as a CD3ε ligand suppressing T cell infiltration established in the Cell paper\",\n      \"pmids\": [\"38188019\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ITPRIPL1 (CD3L1) functions as a cell-surface inhibitory ligand that binds CD3ε on T cells through its extracellular domain, directly suppressing the initial phase of T cell activation by reducing calcium influx and ZAP70 phosphorylation, thereby enabling tumor immune evasion; neutralizing antibodies against ITPRIPL1 restore T cell infiltration and suppress tumor growth in vivo.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ITPRIPL1 (also termed CD3L1) is a cell-surface inhibitory ligand that binds CD3ε on T cells through its extracellular domain, suppressing the initial phase of T cell activation by reducing calcium influx and ZAP70 phosphorylation [PMID:38614099]. ITPRIPL1 is overexpressed in non-small cell lung cancer, where its expression inversely correlates with CD8+ T cell infiltration, consistent with a role in tumor immune evasion [PMID:38188019]. Neutralizing antibodies against ITPRIPL1 restore T cell infiltration and suppress tumor growth in vivo, establishing it as a functional immune checkpoint [PMID:38614099].\",\n  \"teleology\": [\n    {\n      \"year\": 2023,\n      \"claim\": \"Establishing that ITPRIPL1 is aberrantly expressed in human tumors and inversely associated with cytotoxic T cell presence provided the first clinical correlate suggesting an immunosuppressive role for this previously uncharacterized protein.\",\n      \"evidence\": \"Immunohistochemistry on NSCLC patient tissue with correlation to CD8+ T cell density\",\n      \"pmids\": [\"38188019\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Correlative IHC without functional manipulation; does not prove causality\",\n        \"Limited to one tumor type (NSCLC)\",\n        \"No mechanistic target on T cells identified\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identification of CD3ε as the direct binding partner of ITPRIPL1 and demonstration that this interaction suppresses proximal TCR signaling (calcium influx, ZAP70 phosphorylation) defined ITPRIPL1 as a bona fide inhibitory immune checkpoint ligand and showed that its blockade restores antitumor immunity in vivo.\",\n      \"evidence\": \"Co-immunoprecipitation/binding assays, calcium flux measurements, ZAP70 phosphorylation assays, neutralizing antibody treatment in mouse tumor models with canine clinical validation\",\n      \"pmids\": [\"38614099\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of the ITPRIPL1–CD3ε interaction is unresolved\",\n        \"Whether ITPRIPL1 signals bidirectionally into the expressing cell is unknown\",\n        \"Relative contribution of ITPRIPL1 versus PD-L1 and other checkpoints in different tumor contexts not established\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural determinants of the ITPRIPL1–CD3ε interface, the breadth of tumor types dependent on this checkpoint, and whether ITPRIPL1 blockade synergizes with existing immunotherapies remain to be defined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No crystal or cryo-EM structure of the ITPRIPL1–CD3ε complex\",\n        \"No systematic pan-cancer functional studies\",\n        \"Combination therapy with anti-PD-1/PD-L1 not formally tested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CD3E\"],\n    \"other_free_text\": []\n  }\n}\n```\n\nWait, I made an error in pathway — I included a GO term. Let me fix that.\n\n```json\n{\n  \"mechanistic_narrative\": \"ITPRIPL1 (also termed CD3L1) is a cell-surface inhibitory ligand that binds CD3ε on T cells through its extracellular domain, suppressing the initial phase of T cell activation by reducing calcium influx and ZAP70 phosphorylation [PMID:38614099]. ITPRIPL1 is overexpressed in non-small cell lung cancer, where its expression inversely correlates with CD8+ T cell infiltration, consistent with a role in tumor immune evasion [PMID:38188019]. Neutralizing antibodies against ITPRIPL1 restore T cell infiltration and suppress tumor growth in vivo, establishing it as a functional immune checkpoint [PMID:38614099].\",\n  \"teleology\": [\n    {\n      \"year\": 2023,\n      \"claim\": \"Establishing that ITPRIPL1 is aberrantly expressed in human tumors and inversely associated with cytotoxic T cell presence provided the first clinical correlate suggesting an immunosuppressive role for this previously uncharacterized protein.\",\n      \"evidence\": \"Immunohistochemistry on NSCLC patient tissue with correlation to CD8+ T cell density\",\n      \"pmids\": [\"38188019\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Correlative IHC without functional manipulation; does not prove causality\",\n        \"Limited to one tumor type (NSCLC)\",\n        \"No mechanistic target on T cells identified\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identification of CD3ε as the direct binding partner of ITPRIPL1 and demonstration that this interaction suppresses proximal TCR signaling (calcium influx, ZAP70 phosphorylation) defined ITPRIPL1 as a bona fide inhibitory immune checkpoint ligand and showed that its blockade restores antitumor immunity in vivo.\",\n      \"evidence\": \"Co-immunoprecipitation/binding assays, calcium flux measurements, ZAP70 phosphorylation assays, neutralizing antibody treatment in mouse tumor models with canine clinical validation\",\n      \"pmids\": [\"38614099\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of the ITPRIPL1–CD3ε interaction is unresolved\",\n        \"Whether ITPRIPL1 signals bidirectionally into the expressing cell is unknown\",\n        \"Relative contribution of ITPRIPL1 versus PD-L1 and other checkpoints in different tumor contexts not established\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural determinants of the ITPRIPL1–CD3ε interface, the breadth of tumor types dependent on this checkpoint, and whether ITPRIPL1 blockade synergizes with existing immunotherapies remain to be defined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No crystal or cryo-EM structure of the ITPRIPL1–CD3ε complex\",\n        \"No systematic pan-cancer functional studies\",\n        \"Combination therapy with anti-PD-1/PD-L1 not formally tested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CD3E\"],\n    \"other_free_text\": []\n  }\n}\n```"}