{"gene":"CDIP1","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2007,"finding":"CDIP1 (CDIP) is a transcriptional target of p53 that induces apoptosis through the extrinsic pathway; CDIP1-dependent apoptosis requires caspase-8 (siRNA knockdown of caspase-8 severely impairs CDIP-dependent cell death), and CDIP1 drives upregulation of TNF-α downstream of p53, establishing a p53→CDIP1→TNF-α apoptotic axis in response to genotoxic stress.","method":"siRNA knockdown, overexpression, luciferase reporter, co-immunoprecipitation, caspase-8 inhibition assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (siRNA, OE, reporter assays) in a single study with clear pathway placement","pmids":["17599062"],"is_preprint":false},{"year":2013,"finding":"Upon ER stress, CDIP1 is induced and physically interacts with BAP31 at the ER membrane; CDIP1 binding to BAP31 is required for BAP31 cleavage, promotes BAP31–Bcl-2 association, and leads to CDIP1-dependent truncated Bid (tBid) generation and caspase-8 activation, ultimately driving BAX oligomerization and mitochondrial apoptosis. Genetic knockout of CDIP1 in mice impairs ER-stress-mediated apoptosis, confirming its essential role in ER-to-mitochondria apoptotic signal transduction.","method":"Co-immunoprecipitation, overexpression, in vitro binding, CDIP1 knockout mice, caspase activity assays, Western blot for BAX oligomerization and tBid","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, genetic KO mouse model, multiple orthogonal readouts; replicated across methods in one study","pmids":["24139803"],"is_preprint":false},{"year":2012,"finding":"Endogenous CDIP1 expression sensitizes cancer cells to TNF-α-induced apoptosis, and CDIP1 acts as a regulator of the p53-mediated death-versus-survival response to TNF-α, favoring pro-apoptotic signaling in vitro and in vivo.","method":"siRNA knockdown, overexpression, in vitro and in vivo tumor models, cell viability assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — clean KD/OE with defined cellular phenotype, in vivo validation, but single lab","pmids":["22549949"],"is_preprint":false},{"year":2020,"finding":"CDIP1 acts as a host cell surface receptor for Bacillus cereus hemolysin BL (HBL) toxin; identified via genome-wide CRISPR-Cas9 knockout screen in LITAF-deficient cells as a second, alternative HBL receptor, functionally distinct from but related to LITAF.","method":"Genome-wide CRISPR-Cas9 knockout screen, LITAF-deficient cell lines, toxin challenge assays, LITAF-deficient mouse model","journal":"Cell host & microbe","confidence":"High","confidence_rationale":"Tier 2 — unbiased genome-wide screen with genetic validation in cells and in vivo mouse model","pmids":["32544461"],"is_preprint":false},{"year":2021,"finding":"CDIP1 interacts with ALG-2 (PDCD6) in a Ca2+-dependent manner and associates with ESCRT-I subunit TSG101; CDIP1 preferentially binds ESCRT-I containing VPS37B or VPS37C partly through ALG-2 as an adaptor. Co-expression of ALG-2 and ESCRT-I enhances CDIP1-induced caspase-3/7-mediated cell death. Additionally, CDIP1 binds VAPA and VAPB through an FFAT-like motif in its C-terminal region, and mutations in this motif reduce CDIP1-induced cell death.","method":"Co-immunoprecipitation of GFP-CDIP1, overexpression, caspase-3/7 activity assays, mutagenesis of FFAT-like motif","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP plus functional mutagenesis, but single lab","pmids":["33503978"],"is_preprint":false},{"year":2024,"finding":"CDIP1 is upregulated by adriamycin in MCF-7 cells and is rapidly degraded via the lysosomal pathway. CDK5 inhibition with roscovitine increases CDIP1 electrophoretic mobility, and a phosphomimetic mutation at Ser-32 of CDIP1 increases apoptosis. CDIP1 expression induces autophagy prior to apoptosis, and inhibition of autophagy (via VPS34 inhibitor SAR405) promotes apoptosis, indicating autophagy acts as a cytoprotective mechanism against CDIP1-induced cell death.","method":"Western blot, pharmacological inhibitors (roscovitine, SAR405), phosphomimetic mutagenesis (S32D), autophagy and apoptosis assays in MCF-7 cells","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 — mutagenesis plus pharmacological dissection with defined cellular phenotype; single lab","pmids":["38928226"],"is_preprint":false},{"year":2021,"finding":"CT exosomal miRNA-21-5p directly targets and silences CDIP1 mRNA in cardiac microvascular endothelial cells, thereby downregulating activated caspase-3 and inhibiting apoptosis under ischemic/hypoxic conditions to promote angiogenesis.","method":"Small RNA sequencing, in vitro miRNA transfection, in vivo rat MI model, immunostaining, molecular knockdown of Cdip1","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro and in vivo functional validation with miRNA/target gene linkage; single lab","pmids":["33391474"],"is_preprint":false}],"current_model":"CDIP1 is a p53-target proapoptotic protein that, upon genotoxic or ER stress, is induced and interacts with BAP31 at the ER membrane to transduce apoptotic signals to mitochondria (via tBid, caspase-8, and BAX oligomerization), sensitizes cells to TNF-α-induced apoptosis through the extrinsic pathway, engages ESCRT-I (via ALG-2) and VAP proteins to further promote caspase-3/7-mediated cell death, is regulated by CDK5-mediated phosphorylation at Ser-32, is subject to lysosomal degradation and counteracted by autophagy, and also functions as an alternative host receptor for the bacterial pore-forming toxin hemolysin BL."},"narrative":{"teleology":[{"year":2007,"claim":"Identification of CDIP1 as a direct p53 transcriptional target established a new link between the p53 tumor-suppressor network and the extrinsic apoptotic pathway, showing that CDIP1-dependent death requires caspase-8 and drives TNF-α upregulation.","evidence":"siRNA knockdown, overexpression, luciferase reporter, caspase-8 inhibition in human cell lines","pmids":["17599062"],"confidence":"High","gaps":["Mechanism by which CDIP1 induces TNF-α expression is not defined","Direct versus indirect transcriptional control of TNF-α by CDIP1 not resolved"]},{"year":2012,"claim":"Demonstrating that endogenous CDIP1 sensitizes cancer cells to TNF-α-induced apoptosis in vitro and in vivo clarified CDIP1 as a functional determinant of cell fate in the p53–TNF-α axis.","evidence":"siRNA knockdown, overexpression, tumor xenograft models, cell viability assays","pmids":["22549949"],"confidence":"Medium","gaps":["Molecular mechanism of TNF-α sensitization (receptor-level vs. intracellular) not dissected","Findings from a single laboratory"]},{"year":2013,"claim":"Showing that CDIP1 physically binds BAP31 at the ER and drives BAP31 cleavage, tBid generation, caspase-8 activation, and BAX oligomerization — confirmed by impaired ER-stress apoptosis in CDIP1 knockout mice — resolved the molecular route by which ER stress signals are relayed to mitochondria through CDIP1.","evidence":"Reciprocal co-immunoprecipitation, in vitro binding, CDIP1 knockout mice, caspase and BAX oligomerization assays","pmids":["24139803"],"confidence":"High","gaps":["Structural basis of the CDIP1–BAP31 interaction is unknown","Whether CDIP1 integrates additional ER-stress sensors upstream is unresolved"]},{"year":2020,"claim":"A genome-wide CRISPR screen revealed an unexpected non-apoptotic function: CDIP1 serves as an alternative host cell-surface receptor for Bacillus cereus hemolysin BL, functionally distinct from but related to LITAF.","evidence":"Genome-wide CRISPR-Cas9 knockout screen in LITAF-deficient cells, toxin challenge, in vivo mouse model","pmids":["32544461"],"confidence":"High","gaps":["Structural determinants of CDIP1–HBL binding are not characterized","Whether toxin binding co-opts CDIP1's apoptotic signaling remains unknown"]},{"year":2021,"claim":"Identification of Ca²⁺-dependent ALG-2 and ESCRT-I (TSG101/VPS37B/C) interactions, together with VAP protein binding through an FFAT-like motif, expanded the CDIP1 interactome and showed that these partners potentiate caspase-3/7-mediated death, linking CDIP1 to ER–endosome membrane contact site machinery.","evidence":"Co-immunoprecipitation of GFP-CDIP1, FFAT-motif mutagenesis, caspase-3/7 activity assays","pmids":["33503978"],"confidence":"Medium","gaps":["Functional significance of ESCRT-I engagement (membrane remodeling vs. signaling platform) not determined","Endogenous validation of ALG-2–CDIP1 complex is lacking","Single laboratory findings"]},{"year":2021,"claim":"Showing that exosomal miR-21-5p silences CDIP1 to suppress caspase-3 activation and apoptosis in cardiac endothelial cells placed CDIP1 within a clinically relevant post-transcriptional regulatory circuit in ischemic heart disease.","evidence":"Small RNA sequencing, miRNA transfection, rat myocardial infarction model","pmids":["33391474"],"confidence":"Medium","gaps":["Whether miR-21-5p regulation of CDIP1 operates broadly or is restricted to cardiac endothelium is unclear","Single laboratory"]},{"year":2024,"claim":"Demonstrating CDK5-dependent phosphorylation at Ser-32, lysosomal degradation, and a cytoprotective autophagy response prior to apoptosis revealed post-translational and autophagic control layers that tune CDIP1 pro-death activity.","evidence":"Roscovitine treatment, S32D phosphomimetic mutagenesis, VPS34 inhibitor SAR405, autophagy and apoptosis assays in MCF-7 cells","pmids":["38928226"],"confidence":"Medium","gaps":["Direct CDK5 phosphorylation of CDIP1 at Ser-32 has not been demonstrated by in vitro kinase assay","Mechanism by which CDIP1 triggers autophagy is undefined","Single laboratory, single cell line"]},{"year":null,"claim":"The structural basis of CDIP1 interactions with BAP31, ESCRT-I, and HBL toxin remains unresolved, and the mechanistic link between CDIP1's roles in apoptosis signaling and its function as a toxin receptor has not been established.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural or cryo-EM data for any CDIP1 complex","Relationship between toxin receptor and apoptotic functions is unexplored","Physiological role of CDK5-mediated Ser-32 phosphorylation in vivo is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1,4]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,1,2,4,5]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[1,5]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[5]}],"complexes":[],"partners":["BCAP31","PDCD6","TSG101","VAPA","VAPB","TP53"],"other_free_text":[]},"mechanistic_narrative":"CDIP1 is a p53-inducible proapoptotic transmembrane protein that transduces death signals from genotoxic and ER stress to mitochondria via the extrinsic apoptotic pathway. Upon induction, CDIP1 interacts with BAP31 at the ER membrane, triggering BAP31 cleavage, caspase-8 activation, generation of truncated Bid (tBid), and BAX oligomerization at mitochondria; CDIP1 knockout mice confirm its essential role in ER-stress-mediated apoptosis [PMID:24139803]. CDIP1 also engages ESCRT-I (via Ca²⁺-dependent ALG-2 binding) and ER-resident VAP proteins through an FFAT-like motif to potentiate caspase-3/7-dependent cell death, while CDK5-mediated phosphorylation at Ser-32 and lysosomal degradation regulate its abundance and activity [PMID:33503978, PMID:38928226]. Beyond apoptosis, CDIP1 drives TNF-α upregulation downstream of p53 to sensitize cells to TNF-α-induced death [PMID:17599062, PMID:22549949] and functions as an alternative host cell-surface receptor for Bacillus cereus hemolysin BL toxin [PMID:32544461]."},"prefetch_data":{"uniprot":{"accession":"Q9H305","full_name":"Cell death-inducing p53-target protein 1","aliases":["Cell death involved p53-target","Cell death-inducing protein","LITAF-like protein","Lipopolysaccharide-induced tumor necrosis factor-alpha-like protein","Transmembrane protein I1"],"length_aa":208,"mass_kda":21.9,"function":"Acts as an important p53/TP53-apoptotic effector. Regulates TNF-mediated apoptosis in a p53/TP53-dependent manner","subcellular_location":"Late endosome membrane; Lysosome membrane","url":"https://www.uniprot.org/uniprotkb/Q9H305/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CDIP1","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":[],"url":"https://opencell.sf.czbiohub.org/search/CDIP1","total_profiled":1310},"omim":[{"mim_id":"610503","title":"CELL DEATH-INDUCING p53 TARGET 1; CDIP1","url":"https://www.omim.org/entry/610503"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Centrosome","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":159.5}],"url":"https://www.proteinatlas.org/search/CDIP1"},"hgnc":{"alias_symbol":["CDIP","LITAFL"],"prev_symbol":["C16orf5"]},"alphafold":{"accession":"Q9H305","domains":[{"cath_id":"-","chopping":"140-204","consensus_level":"medium","plddt":57.5498,"start":140,"end":204}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H305","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H305-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H305-F1-predicted_aligned_error_v6.png","plddt_mean":55.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CDIP1","jax_strain_url":"https://www.jax.org/strain/search?query=CDIP1"},"sequence":{"accession":"Q9H305","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H305.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H305/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H305"}},"corpus_meta":[{"pmid":"33391474","id":"PMC_33391474","title":"Cardiac telocytes inhibit cardiac microvascular endothelial cell apoptosis through exosomal miRNA-21-5p-targeted cdip1 silencing to improve angiogenesis following myocardial infarction.","date":"2021","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/33391474","citation_count":141,"is_preprint":false},{"pmid":"24139803","id":"PMC_24139803","title":"CDIP1-BAP31 complex transduces apoptotic signals from endoplasmic reticulum to mitochondria under endoplasmic reticulum stress.","date":"2013","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/24139803","citation_count":83,"is_preprint":false},{"pmid":"17599062","id":"PMC_17599062","title":"CDIP, a novel pro-apoptotic gene, regulates TNFalpha-mediated apoptosis in a p53-dependent manner.","date":"2007","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/17599062","citation_count":36,"is_preprint":false},{"pmid":"32544461","id":"PMC_32544461","title":"Sequential CRISPR-Based Screens Identify LITAF and CDIP1 as the Bacillus cereus Hemolysin BL Toxin Host Receptors.","date":"2020","source":"Cell host & microbe","url":"https://pubmed.ncbi.nlm.nih.gov/32544461","citation_count":24,"is_preprint":false},{"pmid":"33737835","id":"PMC_33737835","title":"IL-33 Promotes the Growth of Non-Small Cell Lung Cancer Cells Through Regulating miR-128-3p/CDIP1 Signalling Pathway.","date":"2021","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/33737835","citation_count":15,"is_preprint":false},{"pmid":"37547727","id":"PMC_37547727","title":"Role of ELK1 in regulating colorectal cancer progression: miR-31-5p/CDIP1 axis in CRC pathogenesis.","date":"2023","source":"PeerJ","url":"https://pubmed.ncbi.nlm.nih.gov/37547727","citation_count":15,"is_preprint":false},{"pmid":"33503978","id":"PMC_33503978","title":"The Novel ALG-2 Target Protein CDIP1 Promotes Cell Death by Interacting with ESCRT-I and VAPA/B.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33503978","citation_count":15,"is_preprint":false},{"pmid":"18336592","id":"PMC_18336592","title":"CDIP-2, a synthetic peptide derived from chemokine (C-C motif) ligand 13 (CCL13), ameliorates allergic airway inflammation.","date":"2008","source":"Clinical and experimental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/18336592","citation_count":13,"is_preprint":false},{"pmid":"22549949","id":"PMC_22549949","title":"Expression of the p53 target CDIP correlates with sensitivity to TNFα-induced apoptosis in cancer cells.","date":"2012","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/22549949","citation_count":11,"is_preprint":false},{"pmid":"24560857","id":"PMC_24560857","title":"A CCL chemokine-derived peptide (CDIP-2) exerts anti-inflammatory activity via CCR1, CCR2 and CCR3 chemokine receptors: Implications as a potential therapeutic treatment of asthma.","date":"2014","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/24560857","citation_count":6,"is_preprint":false},{"pmid":"10570909","id":"PMC_10570909","title":"C16orf5, a novel proline-rich gene at 16p13.3, is highly expressed in the brain.","date":"1999","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10570909","citation_count":5,"is_preprint":false},{"pmid":"38928226","id":"PMC_38928226","title":"Cytoprotective Role of Autophagy in CDIP1 Expression-Induced Apoptosis in MCF-7 Breast Cancer Cells.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38928226","citation_count":2,"is_preprint":false},{"pmid":"35680997","id":"PMC_35680997","title":"CDiP technology for reverse engineering of sporadic Alzheimer's disease.","date":"2022","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35680997","citation_count":2,"is_preprint":false},{"pmid":"37589034","id":"PMC_37589034","title":"IL-33 Promotes the Growth of Non-Small Cell Lung Cancer Cells Through Regulating miR-128-3p/CDIP1 Signalling Pathway [Retraction].","date":"2023","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/37589034","citation_count":0,"is_preprint":false},{"pmid":"39483909","id":"PMC_39483909","title":"Metabolic rewiring in fat-depleted Drosophila reveals triglyceride:glycogen crosstalk and identifies cDIP as a new regulator of energy metabolism.","date":"2024","source":"Research square","url":"https://pubmed.ncbi.nlm.nih.gov/39483909","citation_count":0,"is_preprint":false},{"pmid":"39943804","id":"PMC_39943804","title":"MiR-133b-3p attenuates angiotensin II-induced cardiac hypertrophy through the inhibition of apoptosis by targeting CDIP1.","date":"2025","source":"Acta biochimica et biophysica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/39943804","citation_count":0,"is_preprint":false},{"pmid":"33833573","id":"PMC_33833573","title":"Erratum: IL-33 Promotes the Growth of Non-Small Cell Lung Cancer Cells Through Regulating miR-128-3p/CDIP1 Signalling Pathway [Corrigendum].","date":"2021","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/33833573","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.04.25.25326448","title":"Evaluation of Oxford Nanopore Technologies workflows for genomic epidemiology of outbreak‐associated bacterial isolates in the clinical setting","date":"2025-04-28","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.25.25326448","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.05.13.593915","title":"Metabolic rewiring in fat-depleted<i>Drosophila</i>reveals triglyceride:glycogen crosstalk and identifies cDIP as a new regulator of energy metabolism","date":"2024-05-14","source":"bioRxiv","url":"https://doi.org/10.1101/2024.05.13.593915","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9867,"output_tokens":1998,"usd":0.029785},"stage2":{"model":"claude-opus-4-6","input_tokens":5282,"output_tokens":2315,"usd":0.126427},"total_usd":0.156212,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"CDIP1 (CDIP) is a transcriptional target of p53 that induces apoptosis through the extrinsic pathway; CDIP1-dependent apoptosis requires caspase-8 (siRNA knockdown of caspase-8 severely impairs CDIP-dependent cell death), and CDIP1 drives upregulation of TNF-α downstream of p53, establishing a p53→CDIP1→TNF-α apoptotic axis in response to genotoxic stress.\",\n      \"method\": \"siRNA knockdown, overexpression, luciferase reporter, co-immunoprecipitation, caspase-8 inhibition assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (siRNA, OE, reporter assays) in a single study with clear pathway placement\",\n      \"pmids\": [\"17599062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Upon ER stress, CDIP1 is induced and physically interacts with BAP31 at the ER membrane; CDIP1 binding to BAP31 is required for BAP31 cleavage, promotes BAP31–Bcl-2 association, and leads to CDIP1-dependent truncated Bid (tBid) generation and caspase-8 activation, ultimately driving BAX oligomerization and mitochondrial apoptosis. Genetic knockout of CDIP1 in mice impairs ER-stress-mediated apoptosis, confirming its essential role in ER-to-mitochondria apoptotic signal transduction.\",\n      \"method\": \"Co-immunoprecipitation, overexpression, in vitro binding, CDIP1 knockout mice, caspase activity assays, Western blot for BAX oligomerization and tBid\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, genetic KO mouse model, multiple orthogonal readouts; replicated across methods in one study\",\n      \"pmids\": [\"24139803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Endogenous CDIP1 expression sensitizes cancer cells to TNF-α-induced apoptosis, and CDIP1 acts as a regulator of the p53-mediated death-versus-survival response to TNF-α, favoring pro-apoptotic signaling in vitro and in vivo.\",\n      \"method\": \"siRNA knockdown, overexpression, in vitro and in vivo tumor models, cell viability assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD/OE with defined cellular phenotype, in vivo validation, but single lab\",\n      \"pmids\": [\"22549949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CDIP1 acts as a host cell surface receptor for Bacillus cereus hemolysin BL (HBL) toxin; identified via genome-wide CRISPR-Cas9 knockout screen in LITAF-deficient cells as a second, alternative HBL receptor, functionally distinct from but related to LITAF.\",\n      \"method\": \"Genome-wide CRISPR-Cas9 knockout screen, LITAF-deficient cell lines, toxin challenge assays, LITAF-deficient mouse model\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — unbiased genome-wide screen with genetic validation in cells and in vivo mouse model\",\n      \"pmids\": [\"32544461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CDIP1 interacts with ALG-2 (PDCD6) in a Ca2+-dependent manner and associates with ESCRT-I subunit TSG101; CDIP1 preferentially binds ESCRT-I containing VPS37B or VPS37C partly through ALG-2 as an adaptor. Co-expression of ALG-2 and ESCRT-I enhances CDIP1-induced caspase-3/7-mediated cell death. Additionally, CDIP1 binds VAPA and VAPB through an FFAT-like motif in its C-terminal region, and mutations in this motif reduce CDIP1-induced cell death.\",\n      \"method\": \"Co-immunoprecipitation of GFP-CDIP1, overexpression, caspase-3/7 activity assays, mutagenesis of FFAT-like motif\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus functional mutagenesis, but single lab\",\n      \"pmids\": [\"33503978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CDIP1 is upregulated by adriamycin in MCF-7 cells and is rapidly degraded via the lysosomal pathway. CDK5 inhibition with roscovitine increases CDIP1 electrophoretic mobility, and a phosphomimetic mutation at Ser-32 of CDIP1 increases apoptosis. CDIP1 expression induces autophagy prior to apoptosis, and inhibition of autophagy (via VPS34 inhibitor SAR405) promotes apoptosis, indicating autophagy acts as a cytoprotective mechanism against CDIP1-induced cell death.\",\n      \"method\": \"Western blot, pharmacological inhibitors (roscovitine, SAR405), phosphomimetic mutagenesis (S32D), autophagy and apoptosis assays in MCF-7 cells\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mutagenesis plus pharmacological dissection with defined cellular phenotype; single lab\",\n      \"pmids\": [\"38928226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CT exosomal miRNA-21-5p directly targets and silences CDIP1 mRNA in cardiac microvascular endothelial cells, thereby downregulating activated caspase-3 and inhibiting apoptosis under ischemic/hypoxic conditions to promote angiogenesis.\",\n      \"method\": \"Small RNA sequencing, in vitro miRNA transfection, in vivo rat MI model, immunostaining, molecular knockdown of Cdip1\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo functional validation with miRNA/target gene linkage; single lab\",\n      \"pmids\": [\"33391474\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CDIP1 is a p53-target proapoptotic protein that, upon genotoxic or ER stress, is induced and interacts with BAP31 at the ER membrane to transduce apoptotic signals to mitochondria (via tBid, caspase-8, and BAX oligomerization), sensitizes cells to TNF-α-induced apoptosis through the extrinsic pathway, engages ESCRT-I (via ALG-2) and VAP proteins to further promote caspase-3/7-mediated cell death, is regulated by CDK5-mediated phosphorylation at Ser-32, is subject to lysosomal degradation and counteracted by autophagy, and also functions as an alternative host receptor for the bacterial pore-forming toxin hemolysin BL.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CDIP1 is a p53-inducible proapoptotic transmembrane protein that transduces death signals from genotoxic and ER stress to mitochondria via the extrinsic apoptotic pathway. Upon induction, CDIP1 interacts with BAP31 at the ER membrane, triggering BAP31 cleavage, caspase-8 activation, generation of truncated Bid (tBid), and BAX oligomerization at mitochondria; CDIP1 knockout mice confirm its essential role in ER-stress-mediated apoptosis [PMID:24139803]. CDIP1 also engages ESCRT-I (via Ca²⁺-dependent ALG-2 binding) and ER-resident VAP proteins through an FFAT-like motif to potentiate caspase-3/7-dependent cell death, while CDK5-mediated phosphorylation at Ser-32 and lysosomal degradation regulate its abundance and activity [PMID:33503978, PMID:38928226]. Beyond apoptosis, CDIP1 drives TNF-α upregulation downstream of p53 to sensitize cells to TNF-α-induced death [PMID:17599062, PMID:22549949] and functions as an alternative host cell-surface receptor for Bacillus cereus hemolysin BL toxin [PMID:32544461].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Identification of CDIP1 as a direct p53 transcriptional target established a new link between the p53 tumor-suppressor network and the extrinsic apoptotic pathway, showing that CDIP1-dependent death requires caspase-8 and drives TNF-α upregulation.\",\n      \"evidence\": \"siRNA knockdown, overexpression, luciferase reporter, caspase-8 inhibition in human cell lines\",\n      \"pmids\": [\"17599062\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which CDIP1 induces TNF-α expression is not defined\",\n        \"Direct versus indirect transcriptional control of TNF-α by CDIP1 not resolved\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrating that endogenous CDIP1 sensitizes cancer cells to TNF-α-induced apoptosis in vitro and in vivo clarified CDIP1 as a functional determinant of cell fate in the p53–TNF-α axis.\",\n      \"evidence\": \"siRNA knockdown, overexpression, tumor xenograft models, cell viability assays\",\n      \"pmids\": [\"22549949\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular mechanism of TNF-α sensitization (receptor-level vs. intracellular) not dissected\",\n        \"Findings from a single laboratory\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showing that CDIP1 physically binds BAP31 at the ER and drives BAP31 cleavage, tBid generation, caspase-8 activation, and BAX oligomerization — confirmed by impaired ER-stress apoptosis in CDIP1 knockout mice — resolved the molecular route by which ER stress signals are relayed to mitochondria through CDIP1.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, in vitro binding, CDIP1 knockout mice, caspase and BAX oligomerization assays\",\n      \"pmids\": [\"24139803\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of the CDIP1–BAP31 interaction is unknown\",\n        \"Whether CDIP1 integrates additional ER-stress sensors upstream is unresolved\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"A genome-wide CRISPR screen revealed an unexpected non-apoptotic function: CDIP1 serves as an alternative host cell-surface receptor for Bacillus cereus hemolysin BL, functionally distinct from but related to LITAF.\",\n      \"evidence\": \"Genome-wide CRISPR-Cas9 knockout screen in LITAF-deficient cells, toxin challenge, in vivo mouse model\",\n      \"pmids\": [\"32544461\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural determinants of CDIP1–HBL binding are not characterized\",\n        \"Whether toxin binding co-opts CDIP1's apoptotic signaling remains unknown\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identification of Ca²⁺-dependent ALG-2 and ESCRT-I (TSG101/VPS37B/C) interactions, together with VAP protein binding through an FFAT-like motif, expanded the CDIP1 interactome and showed that these partners potentiate caspase-3/7-mediated death, linking CDIP1 to ER–endosome membrane contact site machinery.\",\n      \"evidence\": \"Co-immunoprecipitation of GFP-CDIP1, FFAT-motif mutagenesis, caspase-3/7 activity assays\",\n      \"pmids\": [\"33503978\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional significance of ESCRT-I engagement (membrane remodeling vs. signaling platform) not determined\",\n        \"Endogenous validation of ALG-2–CDIP1 complex is lacking\",\n        \"Single laboratory findings\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showing that exosomal miR-21-5p silences CDIP1 to suppress caspase-3 activation and apoptosis in cardiac endothelial cells placed CDIP1 within a clinically relevant post-transcriptional regulatory circuit in ischemic heart disease.\",\n      \"evidence\": \"Small RNA sequencing, miRNA transfection, rat myocardial infarction model\",\n      \"pmids\": [\"33391474\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether miR-21-5p regulation of CDIP1 operates broadly or is restricted to cardiac endothelium is unclear\",\n        \"Single laboratory\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrating CDK5-dependent phosphorylation at Ser-32, lysosomal degradation, and a cytoprotective autophagy response prior to apoptosis revealed post-translational and autophagic control layers that tune CDIP1 pro-death activity.\",\n      \"evidence\": \"Roscovitine treatment, S32D phosphomimetic mutagenesis, VPS34 inhibitor SAR405, autophagy and apoptosis assays in MCF-7 cells\",\n      \"pmids\": [\"38928226\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct CDK5 phosphorylation of CDIP1 at Ser-32 has not been demonstrated by in vitro kinase assay\",\n        \"Mechanism by which CDIP1 triggers autophagy is undefined\",\n        \"Single laboratory, single cell line\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of CDIP1 interactions with BAP31, ESCRT-I, and HBL toxin remains unresolved, and the mechanistic link between CDIP1's roles in apoptosis signaling and its function as a toxin receptor has not been established.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural or cryo-EM data for any CDIP1 complex\",\n        \"Relationship between toxin receptor and apoptotic functions is unexplored\",\n        \"Physiological role of CDK5-mediated Ser-32 phosphorylation in vivo is unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1, 4]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 1, 2, 4, 5]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"BCAP31\",\n      \"PDCD6\",\n      \"TSG101\",\n      \"VAPA\",\n      \"VAPB\",\n      \"TP53\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}