{"gene":"ITPRIP","run_date":"2026-06-14T21:09:34+00:00","timeline":{"discoveries":[{"year":2021,"finding":"Upregulation of ITPRIP (inositol 1,4,5-trisphosphate receptor interacting protein) in HEK293 producer cells, identified via genome-wide CRISPR transcriptional activation screen, increased AAV vector genomic replication and loading into AAV virions, resulting in up to 3.8-fold increase in AAV manufacturing capacity, establishing a functional role for ITPRIP in viral vector packaging.","method":"Genome-wide CRISPR-based transcriptional activation screen; stable producer cell lines with individual/combinatorial target modulation; measurement of vector genomic replication and virion loading","journal":"Molecular therapy. Nucleic acids","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean gain-of-function with defined cellular phenotype (AAV production increase), single lab, single study, no orthogonal mechanistic dissection of how ITPRIP affects replication/packaging","pmids":["34513296"],"is_preprint":false}],"current_model":"ITPRIP (DANGER) has been shown experimentally to promote AAV vector genomic replication and packaging when upregulated in HEK293 cells; no direct molecular mechanism linking it to its namesake IP3 receptor interaction has been established in the available literature."},"narrative":{"mechanistic_narrative":"ITPRIP (DANGER) has a functional role in adeno-associated viral (AAV) vector production: upregulation of ITPRIP in HEK293 producer cells, identified through a genome-wide CRISPR transcriptional activation screen, increased AAV vector genomic replication and loading into virions, yielding up to a 3.8-fold gain in manufacturing capacity [PMID:34513296]. Beyond this gain-of-function phenotype, no direct molecular mechanism—including any interaction with its namesake IP3 receptor—has been characterized in the available corpus.","teleology":[{"year":2021,"claim":"Whether host-cell factors could be engineered to boost AAV vector manufacturing was unresolved; a genome-wide activation screen identified ITPRIP upregulation as a driver of increased AAV genomic replication and virion packaging, establishing a functional role in viral vector production.","evidence":"Genome-wide CRISPR transcriptional activation screen in HEK293 producer cells with stable target modulation and measurement of vector genomic replication and virion loading","pmids":["34513296"],"confidence":"Medium","gaps":["Single lab, single study with no orthogonal mechanistic dissection of how ITPRIP affects replication or packaging","No molecular link established between ITPRIP and the IP3 receptor or any defined biochemical activity","Subcellular localization and direct physical partners during AAV production not determined"]},{"year":null,"claim":"The molecular mechanism by which ITPRIP promotes AAV genomic replication and packaging, and its native cellular function, remain undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No biochemical activity or substrate identified","No structural model or interaction partner characterized","Relationship to namesake IP3 receptor interaction unestablished in the corpus"]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IWB1","full_name":"Inositol 1,4,5-trisphosphate receptor-interacting protein","aliases":["Protein DANGER"],"length_aa":547,"mass_kda":62.1,"function":"Enhances Ca(2+)-mediated inhibition of inositol 1,4,5-triphosphate receptor (ITPR) Ca(2+) release","subcellular_location":"Cell membrane; Nucleus outer membrane","url":"https://www.uniprot.org/uniprotkb/Q8IWB1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ITPRIP","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":[{"gene":"VPS8","stoichiometry":10.0},{"gene":"PGRMC2","stoichiometry":0.2},{"gene":"STK4","stoichiometry":0.2},{"gene":"VAPA","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ITPRIP","total_profiled":1310},"omim":[{"mim_id":"621465","title":"ITPRIP-LIKE PROTEIN 2; ITPRIPL2","url":"https://www.omim.org/entry/621465"},{"mim_id":"620821","title":"ITPRIP-LIKE PROTEIN 1; ITPRIPL1","url":"https://www.omim.org/entry/620821"},{"mim_id":"620205","title":"INOSITOL 1,4,5-TRISPHOSPHATE RECEPTOR-INTERACTING PROTEIN; ITPRIP","url":"https://www.omim.org/entry/620205"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Vesicles","reliability":"Uncertain"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"bone marrow","ntpm":192.1}],"url":"https://www.proteinatlas.org/search/ITPRIP"},"hgnc":{"alias_symbol":["bA127L20.2","DANGER","D1A"],"prev_symbol":["KIAA1754"]},"alphafold":{"accession":"Q8IWB1","domains":[{"cath_id":"3.30.460.90","chopping":"133-248_284-368_375-537","consensus_level":"medium","plddt":88.2961,"start":133,"end":537}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IWB1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IWB1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IWB1-F1-predicted_aligned_error_v6.png","plddt_mean":78.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ITPRIP","jax_strain_url":"https://www.jax.org/strain/search?query=ITPRIP"},"sequence":{"accession":"Q8IWB1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IWB1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IWB1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IWB1"}},"corpus_meta":[{"pmid":"23602987","id":"PMC_23602987","title":"BDNF-induced local protein synthesis and synaptic plasticity.","date":"2013","source":"Neuropharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/23602987","citation_count":547,"is_preprint":false},{"pmid":"23872332","id":"PMC_23872332","title":"Somatostatin receptors: from signaling to clinical practice.","date":"2013","source":"Frontiers in neuroendocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/23872332","citation_count":325,"is_preprint":false},{"pmid":"23827971","id":"PMC_23827971","title":"Impaired autophagy and APP processing in Alzheimer's disease: The potential role of Beclin 1 interactome.","date":"2013","source":"Progress in neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/23827971","citation_count":313,"is_preprint":false},{"pmid":"23348743","id":"PMC_23348743","title":"Blockade of NOX2 and STIM1 signaling limits lipopolysaccharide-induced vascular inflammation.","date":"2013","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/23348743","citation_count":200,"is_preprint":false},{"pmid":"34513296","id":"PMC_34513296","title":"Genome-wide activation screens to increase adeno-associated virus production.","date":"2021","source":"Molecular therapy. Nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/34513296","citation_count":27,"is_preprint":false},{"pmid":"25066731","id":"PMC_25066731","title":"Receptor-interacting protein 140 attenuates endoplasmic reticulum stress in neurons and protects against cell death.","date":"2014","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/25066731","citation_count":23,"is_preprint":false},{"pmid":"18627437","id":"PMC_18627437","title":"Sweet taste receptor interacting protein CIB1 is a general inhibitor of InsP3-dependent Ca2+ release in vivo.","date":"2008","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18627437","citation_count":22,"is_preprint":false},{"pmid":"39211744","id":"PMC_39211744","title":"A comprehensive pan-cancer analysis revealing the role of ITPRIPL1 as a prognostic and immunological biomarker.","date":"2024","source":"Frontiers in molecular biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/39211744","citation_count":4,"is_preprint":false},{"pmid":"41365494","id":"PMC_41365494","title":"Integrated Multiomics Analysis and Experimental Validation Identify ITPRIPL1 as an Immunoregulatory and Prognostic Biomarker in Gastric Adenocarcinoma.","date":"2025","source":"Journal of gastroenterology and hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/41365494","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"sonnet_model":"claude-sonnet-4-6","sonnet_input_tokens":6521,"sonnet_output_tokens":660,"sonnet_usd":0.0295,"sonnet_elapsed_seconds":14.3,"stage1_stop_reason":"end_turn"},"stage2":{"opus_model":"claude-opus-4-8","opus_input_tokens":6609,"opus_output_tokens":782,"opus_usd":0.0526,"opus_elapsed_seconds":9.8,"stage2_stop_reason":"end_turn"},"total_usd":0.0821},"stage1_raw":"Looking at the papers:\n\n- Papers [1], [2], [3], [4]: General reviews/studies about BDNF, somatostatin receptors, Beclin 1, and STIM1 - no mechanistic findings about ITPRIP.\n- Paper [5]: About ITPRIP (inositol 1,4,5-trisphosphate receptor interacting protein) in AAV production - this is the canonical ITPRIP gene. Contains a mechanistic finding about ITPRIP's role in AAV packaging.\n- Paper [6]: About RIP140 (receptor-interacting protein 140, also called NRIP1) interacting with IP3R - this is NOT ITPRIP/DANGER. This is a different protein (RIP140/NRIP1). Skip.\n- Paper [7]: About CIB1 interacting with InsP3 receptor - not about ITPRIP. Skip.\n- Papers [8], [9]: About ITPRIPL1 (inositol 1,4,5-trisphosphate receptor-interacting protein-LIKE 1) - this is a PARALOG, not ITPRIP itself. Skip.\n\nOnly paper [5] is relevant and describes a mechanistic finding about ITPRIP.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2021,\n      \"finding\": \"Upregulation of ITPRIP (inositol 1,4,5-trisphosphate receptor interacting protein) in HEK293 producer cells, identified via genome-wide CRISPR transcriptional activation screen, increased AAV vector genomic replication and loading into AAV virions, resulting in up to 3.8-fold increase in AAV manufacturing capacity, establishing a functional role for ITPRIP in viral vector packaging.\",\n      \"method\": \"Genome-wide CRISPR-based transcriptional activation screen; stable producer cell lines with individual/combinatorial target modulation; measurement of vector genomic replication and virion loading\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean gain-of-function with defined cellular phenotype (AAV production increase), single lab, single study, no orthogonal mechanistic dissection of how ITPRIP affects replication/packaging\",\n      \"pmids\": [\"34513296\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ITPRIP (DANGER) has been shown experimentally to promote AAV vector genomic replication and packaging when upregulated in HEK293 cells; no direct molecular mechanism linking it to its namesake IP3 receptor interaction has been established in the available literature.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ITPRIP (DANGER) has a functional role in adeno-associated viral (AAV) vector production: upregulation of ITPRIP in HEK293 producer cells, identified through a genome-wide CRISPR transcriptional activation screen, increased AAV vector genomic replication and loading into virions, yielding up to a 3.8-fold gain in manufacturing capacity [#0]. Beyond this gain-of-function phenotype, no direct molecular mechanism—including any interaction with its namesake IP3 receptor—has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2021,\n      \"claim\": \"Whether host-cell factors could be engineered to boost AAV vector manufacturing was unresolved; a genome-wide activation screen identified ITPRIP upregulation as a driver of increased AAV genomic replication and virion packaging, establishing a functional role in viral vector production.\",\n      \"evidence\": \"Genome-wide CRISPR transcriptional activation screen in HEK293 producer cells with stable target modulation and measurement of vector genomic replication and virion loading\",\n      \"pmids\": [\"34513296\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single lab, single study with no orthogonal mechanistic dissection of how ITPRIP affects replication or packaging\",\n        \"No molecular link established between ITPRIP and the IP3 receptor or any defined biochemical activity\",\n        \"Subcellular localization and direct physical partners during AAV production not determined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular mechanism by which ITPRIP promotes AAV genomic replication and packaging, and its native cellular function, remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No biochemical activity or substrate identified\",\n        \"No structural model or interaction partner characterized\",\n        \"Relationship to namesake IP3 receptor interaction unestablished in the corpus\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"loss"}}