{"gene":"CDS2","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":1997,"finding":"CDS2 encodes a second human CDP-diacylglycerol synthase (CDS) isoform that converts phosphatidic acid to CDP-diacylglycerol; its existence was inferred from EST database screening alongside CDS1, with both enzymes localized to the ER and their overexpression shown not to be rate-limiting for cellular phosphatidylinositol content.","method":"cDNA cloning from EST database, expression in COS-7 cells, in vitro enzyme activity assay, Northern blot","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro enzymatic activity demonstrated, functional expression in mammalian cells, replicated by independent cloning papers","pmids":["9407135"],"is_preprint":false},{"year":1998,"finding":"Human CDS2 gene was cloned, sequenced, and mapped to chromosome 20p13 by radiation hybrid panel mapping and FISH; the encoded protein is homologous to Drosophila CDP-diacylglycerol synthase required for phototransduction.","method":"cDNA cloning, radiation hybrid mapping, fluorescence in situ hybridization (FISH)","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 2 — direct chromosomal mapping with two independent methods in a peer-reviewed study","pmids":["9806839"],"is_preprint":false},{"year":1999,"finding":"CDS2 full-length cDNA was isolated and shown to encode a protein 64.4% identical to Drosophila CDS; in situ hybridization showed Cds2 is highly expressed in differentiating neuroblasts of the neural retina and CNS during embryonic mouse development but absent from adult retina.","method":"cDNA isolation, sequence analysis, RNA in situ hybridization on mouse tissue sections","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 2 — direct localization by in situ hybridization with developmental context established","pmids":["9889000"],"is_preprint":false},{"year":2003,"finding":"PPARα activation in mouse heart in vivo upregulates CDS-2 activity and mRNA levels and stimulates cardiolipin de novo biosynthesis; this regulation was absent in PPARα-null mice, placing CDS2 downstream of PPARα in cardiac cardiolipin synthesis.","method":"Clofibrate treatment of wild-type and PPARα-null mice, CDS-2 enzyme activity assay, mRNA quantification, cardiolipin biosynthesis assay","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis using knockout mice plus enzyme activity assays in multiple model systems","pmids":["14594999"],"is_preprint":false},{"year":2005,"finding":"Murine Cds2 (and Cds1) proteins were shown by transient transfection with epitope-tagged constructs to localize to the endoplasmic reticulum; Cds2 exhibits ubiquitous expression while Cds1 is restricted, and the two proteins are 73% identical.","method":"Fluorescence microscopy of epitope-tagged proteins in transiently transfected cells, RT-PCR expression analysis, FISH chromosomal mapping","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 3 — subcellular localization by overexpressed tagged protein without functional consequence demonstrated","pmids":["16023307"],"is_preprint":false},{"year":2009,"finding":"CDS-2 shRNA knockdown in HepG2/HEK293T cells disrupted cardiolipin biosynthesis and abolished mitomycin C-induced mitochondrial translocation of p53, demonstrating that CDS2-dependent cardiolipin synthesis is required for p53 mitochondrial localization and its downstream regulation of Bcl-xL and Bcl-2.","method":"shRNA knockdown, immunoblot fractionation of mitochondria, cardiolipin biosynthesis disruption assay","journal":"Neoplasia","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with specific organellar fractionation readout; single study","pmids":["20126473"],"is_preprint":false},{"year":2009,"finding":"In FATP-1-overexpressing HEK293 cells, CDS-2 mRNA expression and CDS enzyme activity were reduced, correlating with decreased cardiolipin synthesis; in vitro CDS activity was inhibited by exogenous oleoyl-CoA, suggesting FATP-1 regulates cardiolipin biosynthesis through CDS-2.","method":"siRNA knockdown and overexpression of FATP-1, CDS enzyme activity assay, mRNA quantification, radiolabeled glycerol incorporation into cardiolipin, in vitro CDS activity with oleoyl-CoA","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro enzyme inhibition assay plus cell-based knockdown/overexpression; single lab","pmids":["19523918"],"is_preprint":false},{"year":2017,"finding":"CDS1 and CDS2 are integral membrane proteins of the ER, while the mitochondrial CDP-diacylglycerol synthase activity previously attributed to CDS1 was traced to the peripheral mitochondrial protein TAMM41; TAMM41 knockdown reduced mitochondrial CDS activity, cardiolipin levels, and oxygen consumption.","method":"Subcellular fractionation, immunoblot, siRNA knockdown of TAMM41, cardiolipin quantification, oxygen consumption measurement, differentiation of H9c2 cells","journal":"Biochimica et biophysica acta. Molecular and cell biology of lipids","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods distinguishing ER vs. mitochondrial localization with functional readout; strong mechanistic insight","pmids":["29253589"],"is_preprint":false},{"year":2016,"finding":"Knockdown of CDS2 (or CDS1) in cultured mammalian cells causes formation of giant/supersized lipid droplets and increases phosphatidic acid levels in the ER; CDS2 depletion had a moderate inhibitory effect on 3T3-L1 adipocyte differentiation.","method":"siRNA knockdown, fluorescence microscopy of lipid droplets, lipidomic analysis of PA species, 3T3-L1 differentiation assay","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 2 — clean knockdown with defined cellular phenotype and lipidomic mechanistic readout; replicated in follow-up study","pmids":["26946540"],"is_preprint":false},{"year":2018,"finding":"p53 physically interacts with SIRT6 in vitro and in vivo, and the complex binds promoters of CDS1 and CDS2 to enhance their transcription; SIRT6 acts as a co-activator recruiting RNA polymerase II to CDS2 promoter, thereby regulating cardiolipin de novo biosynthesis.","method":"Co-immunoprecipitation (in vitro and in vivo), chromatin immunoprecipitation (ChIP), reporter assays, palmitic acid treatment","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal Co-IP plus ChIP establishing direct transcriptional regulation; single lab","pmids":["30237540"],"is_preprint":false},{"year":2019,"finding":"Genetic ablation of CDS2 in zebrafish and mouse endothelium switches VEGFA signaling from pro-angiogenic to pro-regressive; mechanistically, VEGFA stimulation in CDS2-null endothelium reduces PIP2 availability, causing PIP3 deficiency and FOXO1 activation that triggers vessel regression.","method":"Zebrafish cds2 mutant live imaging, conditional mouse CDS2 knockout (retina and tumor models), PIP2/PIP3 measurements, FOXO1 activation assay","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 2 — multiple model systems (zebrafish, mouse retina, tumor), live imaging, and defined signaling pathway established","pmids":["31501519"],"is_preprint":false},{"year":2019,"finding":"CDS2, but not CDS1, contributes to increased PI resynthesis during PLC activation; CDS2 preferentially routes arachidonoyl-enriched PA species toward PI synthesis, contributing to maintenance of the 38:4 fatty acid profile of phosphoinositides during agonist stimulation.","method":"Stable isotope labeling (13C-glucose), mass spectrometry of PI species, siRNA knockdown of CDS2 vs CDS1, agonist-stimulated PLC assays","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1 — stable isotope tracing with mass spectrometry plus specific gene knockdowns distinguishing CDS1 vs CDS2 roles","pmids":["35712788"],"is_preprint":false},{"year":2019,"finding":"CDS2 deficiency (but not CDS1 deficiency) promotes LD association of DGAT2 and GPAT4 and impairs initial LD maturation; reducing DGAT2 or GPAT4 expression rescued the giant LD phenotype in CDS2-deficient cells but not CDS1-deficient cells, revealing distinct mechanisms for CDS1 vs CDS2 in LD growth.","method":"siRNA knockdown, CRISPR/Cas9 knockout, fluorescence microscopy, immunological localization of DGAT2/GPAT4 at LDs","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — CRISPR KO plus epistasis (double knockdown rescue) distinguishing molecular mechanisms; replicated across two labs","pmids":["31548309"],"is_preprint":false},{"year":2021,"finding":"Liver-specific CDS2 deficiency in mice caused hepatic steatosis, inflammation, and fibrosis; CDS2 is enriched in mitochondria-associated membranes (MAMs) and its loss impairs mitochondrial function and decreases mitochondrial PE levels; overexpression of PISD (phosphatidylserine decarboxylase) rescued the NASH-like phenotype, placing CDS2 upstream of mitochondrial PE synthesis.","method":"Liver-specific Cds2 knockout mice, MAM fractionation, mitochondrial function assays, lipidomics, PISD overexpression rescue, PPARα agonist treatment","journal":"Science bulletin","confidence":"High","confidence_rationale":"Tier 2 — conditional KO mouse model with organellar fractionation, lipidomics, and genetic rescue establishing pathway position","pmids":["36546079"],"is_preprint":false},{"year":2024,"finding":"In primary mouse macrophages, CDS2 deletion causes modest changes in steady-state PI but substantially increases PA, CDP-DG, DG, and TG; stable isotope labeling showed CDS2 loss minimally reduces de novo PI synthesis rate but substantially increases de novo PA synthesis from G3P. Under sustained PLC stimulation, CDS2-deficient macrophages cannot maintain enhanced PI synthesis ('PI cycle'), causing PI depletion; CDS2 deficiency also causes calcium homeostasis defects independent of PLC activation.","method":"CRISPR/Cas9 knockout in primary macrophages, stable isotope labeling (13C6-glucose, 13C6D7-glucose), lipidomics, GPCR-stimulated PLC assays, calcium imaging","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 — stable isotope tracing plus KO in primary cells with multiple orthogonal readouts; single but rigorous study","pmids":["39312194"],"is_preprint":false},{"year":2025,"finding":"CDS2 is a synthetic lethal target in the context of low CDS1 expression in uveal melanoma and multiple tumor types; CDS2 knockout disrupts phosphoinositide synthesis and increases cellular apoptosis; re-expression of CDS1 rescues the cell fitness defect; synthetic lethality depends on CDS2 catalytic activity and operates in vivo.","method":"Genome-wide CRISPR-Cas9 single and paired-gene screens in 10 uveal melanoma cell lines, CDS1 re-expression rescue, in vivo tumor models, pan-cancer data analysis","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 — genome-scale CRISPR screen plus mechanistic rescue experiments in multiple cell lines and in vivo models; two independent papers in the same journal issue","pmids":["40615675"],"is_preprint":false},{"year":2025,"finding":"CDS2 essentiality in mesenchymal-like (CDS1-low) cancers is accompanied by disruption of lipid homeostasis including accumulation of cholesterol esters and triglycerides; synthetic lethality is driven by CDS2 dosage and requires catalytic activity; no common CRISPR escape mechanism was identified, indicating robustness of the interaction.","method":"Genome-wide CRISPR-Cas9 KO screens in CDS1-negative cancer cells, lipidomics, catalytic mutant rescue experiments","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 1–2 — catalytic mutant rescue plus genome-wide screen and lipidomics; independent replication of CDS1/CDS2 SLI in companion paper","pmids":["40615674"],"is_preprint":false},{"year":2025,"finding":"Under physiological conditions MBOAT7 interacts with CDS2 at the ER to maintain lipid metabolic homeostasis; CDS2 knockdown or loss of function triggers MBOAT7 translocation from ER to ER-LD contact sites in a RAB1-dependent manner, where it inhibits DGAT2-mediated LD growth and promotes lipolysis.","method":"Co-immunoprecipitation, fluorescence microscopy of MBOAT7 localization, CDS2 knockdown, RAB1 dependency assay, LD size measurement, lipolysis assay","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP plus live-cell localization and functional rescue; preprint, not yet peer-reviewed","pmids":["bio_10.1101_2025.08.26.672501"],"is_preprint":true}],"current_model":"CDS2 is an integral ER membrane enzyme that converts phosphatidic acid to CDP-diacylglycerol, serving as the rate-limiting step for phosphatidylinositol (PI) resynthesis during PLC signaling—particularly for arachidonoyl-enriched PI species—and is a synthetic lethal partner with its paralog CDS1, such that CDS2 loss in CDS1-low contexts disrupts phosphoinositide homeostasis, elevates PA/DG/TG, triggers apoptosis, promotes giant lipid droplet formation via DGAT2/GPAT4 recruitment, and in endothelial cells causes VEGFA-driven vessel regression through PIP2/PIP3 depletion and FOXO1 activation; its expression is regulated transcriptionally by p53-SIRT6 and PPARα, and it localizes to mitochondria-associated membranes where it supports mitochondrial PE levels and function."},"narrative":{"teleology":[{"year":1997,"claim":"Identification of CDS2 as a second mammalian CDP-diacylglycerol synthase established that PA-to-CDP-DAG conversion is catalyzed by two distinct isoforms, raising the question of whether they serve redundant or specialized roles.","evidence":"cDNA cloning from EST database, expression in COS-7 cells with in vitro enzyme activity assay","pmids":["9407135"],"confidence":"High","gaps":["No isoform-specific substrates or regulation identified","Overexpression did not limit PI content, leaving physiological rate-limiting role unclear"]},{"year":2003,"claim":"Demonstration that PPARα activates CDS2 transcription and CDS2-dependent cardiolipin biosynthesis in heart tissue established the first transcriptional regulator of CDS2 and linked it to cardiac mitochondrial lipid metabolism.","evidence":"Clofibrate treatment of wild-type vs. PPARα-null mice with CDS-2 enzyme activity and mRNA quantification","pmids":["14594999"],"confidence":"High","gaps":["Whether PPARα directly binds CDS2 promoter or acts indirectly was not resolved","Cardiac-specific role versus systemic relevance unclear"]},{"year":2009,"claim":"CDS2 knockdown disrupted cardiolipin biosynthesis and abolished mitomycin C-induced p53 mitochondrial translocation, revealing CDS2 as required for a stress-activated apoptotic signaling step.","evidence":"shRNA knockdown in HepG2/HEK293T cells with mitochondrial fractionation and immunoblot","pmids":["20126473"],"confidence":"Medium","gaps":["Single study without independent replication","Whether cardiolipin itself or downstream lipid changes mediate p53 translocation was not distinguished"]},{"year":2016,"claim":"CDS2 depletion was shown to cause giant lipid droplet formation and ER phosphatidic acid accumulation, establishing that CDS2 controls PA flux away from neutral lipid storage pathways.","evidence":"siRNA knockdown with fluorescence microscopy and lipidomic analysis of PA species","pmids":["26946540"],"confidence":"High","gaps":["Mechanism by which elevated PA drives giant LD formation not yet defined","CDS1 vs CDS2 specificity in LD phenotype not resolved in this study"]},{"year":2017,"claim":"Definitive ER localization of CDS1/CDS2 was established by showing that mitochondrial CDP-DAG synthase activity belongs to TAMM41, not CDS2, resolving a longstanding compartmental ambiguity.","evidence":"Subcellular fractionation, siRNA knockdown of TAMM41, cardiolipin and oxygen consumption measurements in H9c2 cells","pmids":["29253589"],"confidence":"High","gaps":["Does not address CDS2 presence at mitochondria-associated membranes (later shown)"]},{"year":2018,"claim":"The p53–SIRT6 complex was shown to directly bind CDS2 promoter and recruit RNA polymerase II, identifying a second transcriptional axis controlling CDS2 expression relevant to cardiolipin metabolism.","evidence":"Co-immunoprecipitation and chromatin immunoprecipitation with reporter assays","pmids":["30237540"],"confidence":"Medium","gaps":["Single laboratory study","Physiological contexts beyond palmitate stress not tested"]},{"year":2019,"claim":"Two key advances distinguished CDS2 from CDS1: (1) CDS2 specifically sustains PI resynthesis during PLC signaling by preferentially routing arachidonoyl-PA toward PI, and (2) CDS2 loss uniquely promotes DGAT2/GPAT4 recruitment to lipid droplets, a phenotype rescued by depleting these enzymes.","evidence":"Stable isotope tracing with mass spectrometry for PI species (CDS2 vs CDS1 knockdown); CRISPR KO plus double-knockdown rescue of giant LD phenotype","pmids":["35712788","31548309"],"confidence":"High","gaps":["Structural basis for CDS2 substrate selectivity toward arachidonoyl-PA unknown","Mechanism linking local PA to DGAT2/GPAT4 recruitment not fully defined"]},{"year":2019,"claim":"Genetic ablation of CDS2 in zebrafish and mouse endothelium converted VEGFA signaling from pro-angiogenic to pro-regressive through PIP2/PIP3 depletion and FOXO1 activation, revealing CDS2 as a vascular-specific gatekeeper of PI-dependent signaling.","evidence":"Zebrafish cds2 mutant live imaging, conditional mouse CDS2 KO in retinal and tumor vasculature, PIP2/PIP3 measurement","pmids":["31501519"],"confidence":"High","gaps":["Whether other PI-dependent pathways (e.g., mTOR) are similarly affected in endothelium not tested","Contribution of CDS1 compensation in vivo not quantified"]},{"year":2021,"claim":"Liver-specific CDS2 deletion caused NASH-like pathology; CDS2 enrichment at mitochondria-associated membranes and rescue by PISD overexpression placed CDS2 upstream of mitochondrial PE synthesis, linking ER CDP-DAG production to mitochondrial membrane lipid homeostasis.","evidence":"Liver-specific Cds2 KO mice, MAM fractionation, lipidomics, PISD genetic rescue","pmids":["36546079"],"confidence":"High","gaps":["How CDP-DAG generated at ER/MAMs feeds into mitochondrial PE synthesis pathway is mechanistically unclear","Whether CDS1 compensates in other tissues not addressed"]},{"year":2024,"claim":"Isotope tracing in primary CDS2-KO macrophages showed that CDS2 is dispensable for basal PI synthesis rates but essential to sustain enhanced PI resynthesis during PLC stimulation, and revealed CDS2 loss causes calcium dysregulation independent of PLC.","evidence":"CRISPR KO in primary macrophages, dual stable isotope labeling, GPCR-stimulated PLC assays, calcium imaging","pmids":["39312194"],"confidence":"High","gaps":["Mechanism of PLC-independent calcium defect not identified","Whether findings extend to non-macrophage immune cells unclear"]},{"year":2025,"claim":"Two independent genome-wide CRISPR screens identified CDS2 as a robust synthetic lethal target in CDS1-low cancers; the interaction depends on CDS2 catalytic activity, operates in vivo, and is accompanied by broad lipid homeostasis disruption including cholesterol ester and triglyceride accumulation.","evidence":"Genome-wide CRISPR screens across uveal melanoma and pan-cancer cell lines, catalytic mutant rescue, CDS1 re-expression rescue, in vivo tumor models, lipidomics","pmids":["40615675","40615674"],"confidence":"High","gaps":["No therapeutic agent targeting CDS2 yet developed","Mechanisms of downstream apoptosis induction beyond lipid imbalance not fully delineated"]},{"year":null,"claim":"The structural basis for CDS2's preference for arachidonoyl-PA substrates, the mechanism by which CDS2-derived CDP-DAG at MAMs supports mitochondrial PE, and whether CDS2 inhibition can be therapeutically exploited in CDS1-low cancers remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No crystal or cryo-EM structure of CDS2","No small-molecule CDS2 inhibitor reported","Precise lipid transfer mechanism from ER/MAM CDP-DAG pool to mitochondrial PE synthesis unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,11,14,15,16]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,4,7,8]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[13]},{"term_id":"GO:0005811","term_label":"lipid droplet","supporting_discovery_ids":[8,12]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,3,8,11,13,14]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[10,11,14]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[5,15]}],"complexes":[],"partners":["CDS1","DGAT2","GPAT4","MBOAT7","SIRT6","TP53"],"other_free_text":[]},"mechanistic_narrative":"CDS2 is an integral endoplasmic reticulum membrane enzyme that catalyzes the conversion of phosphatidic acid (PA) to CDP-diacylglycerol (CDP-DAG), serving as the committed step for phosphatidylinositol (PI) resynthesis during phospholipase C signaling. CDS2 preferentially channels arachidonoyl-enriched PA species toward PI synthesis and is specifically required to sustain the PI cycle during agonist-stimulated PLC activation; its loss causes PA, diacylglycerol, and triglyceride accumulation, giant lipid droplet formation via DGAT2/GPAT4 recruitment, and calcium homeostasis defects [PMID:35712788, PMID:39312194, PMID:31548309, PMID:26946540]. CDS2 localizes to mitochondria-associated membranes where it supports mitochondrial phosphatidylethanolamine levels, and liver-specific CDS2 deletion causes hepatic steatosis, inflammation, and fibrosis [PMID:36546079]. CDS2 is a robust synthetic lethal partner of its paralog CDS1, such that CDS2 loss in CDS1-low cancers disrupts phosphoinositide homeostasis and triggers apoptosis in a catalytic-activity-dependent manner [PMID:40615675, PMID:40615674]."},"prefetch_data":{"uniprot":{"accession":"O95674","full_name":"Phosphatidate cytidylyltransferase 2","aliases":["CDP-DAG synthase 2","CDP-DG synthase 2","CDP-diacylglycerol synthase 2","CDS 2","CDP-diglyceride pyrophosphorylase 2","CDP-diglyceride synthase 2","CTP:phosphatidate cytidylyltransferase 2"],"length_aa":445,"mass_kda":51.4,"function":"Catalyzes the conversion of phosphatidic acid (PA) to CDP-diacylglycerol (CDP-DAG), an essential intermediate in the synthesis of phosphatidylglycerol, cardiolipin and phosphatidylinositol (PubMed:25375833). Exhibits specificity for the nature of the acyl chains at the sn-1 and sn-2 positions in the substrate, PA and the preferred acyl chain composition is 1-stearoyl-2-arachidonoyl-sn-phosphatidic acid (PubMed:25375833). Plays an important role in regulating the growth and maturation of lipid droplets which are storage organelles at the center of lipid and energy homeostasis (PubMed:26946540, PubMed:31548309)","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/O95674/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CDS2","classification":"Not Classified","n_dependent_lines":367,"n_total_lines":1208,"dependency_fraction":0.3038079470198676},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000101290","cell_line_id":"CID000345","localizations":[{"compartment":"er","grade":3},{"compartment":"vesicles","grade":3}],"interactors":[{"gene":"CDS1","stoichiometry":10.0},{"gene":"PGRMC1","stoichiometry":4.0},{"gene":"ALDH3A2","stoichiometry":0.2},{"gene":"SSR4","stoichiometry":0.2},{"gene":"EMD","stoichiometry":0.2},{"gene":"SLC6A8","stoichiometry":0.2},{"gene":"SLMAP","stoichiometry":0.2},{"gene":"SRPRB","stoichiometry":0.2},{"gene":"VAPA","stoichiometry":0.2},{"gene":"ASPH","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000345","total_profiled":1310},"omim":[{"mim_id":"605893","title":"CDP-DIACYLGLYCEROL-INOSITOL 3-PHOSPHATIDYLTRANSFERASE; CDIPT","url":"https://www.omim.org/entry/605893"},{"mim_id":"603549","title":"CDP-DIACYLGLYCEROL SYNTHASE 2; CDS2","url":"https://www.omim.org/entry/603549"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Endoplasmic reticulum","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CDS2"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"O95674","domains":[{"cath_id":"-","chopping":"406-445","consensus_level":"medium","plddt":80.896,"start":406,"end":445}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O95674","model_url":"https://alphafold.ebi.ac.uk/files/AF-O95674-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O95674-F1-predicted_aligned_error_v6.png","plddt_mean":81.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CDS2","jax_strain_url":"https://www.jax.org/strain/search?query=CDS2"},"sequence":{"accession":"O95674","fasta_url":"https://rest.uniprot.org/uniprotkb/O95674.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O95674/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O95674"}},"corpus_meta":[{"pmid":"11682368","id":"PMC_11682368","title":"Performance of comorbidity scores to control for confounding in epidemiologic studies using claims data.","date":"2001","source":"American journal of epidemiology","url":"https://pubmed.ncbi.nlm.nih.gov/11682368","citation_count":623,"is_preprint":false},{"pmid":"23299975","id":"PMC_23299975","title":"MMAPPR: mutation mapping analysis pipeline for pooled RNA-seq.","date":"2013","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/23299975","citation_count":280,"is_preprint":false},{"pmid":"19571312","id":"PMC_19571312","title":"Abscisic acid has a key role in modulating diverse plant-pathogen interactions.","date":"2009","source":"Plant physiology","url":"https://pubmed.ncbi.nlm.nih.gov/19571312","citation_count":236,"is_preprint":false},{"pmid":"17000729","id":"PMC_17000729","title":"Identification of MglA-regulated genes reveals novel virulence factors in Francisella tularensis.","date":"2006","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/17000729","citation_count":139,"is_preprint":false},{"pmid":"22524474","id":"PMC_22524474","title":"High levels of RNA-editing site conservation amongst 15 laboratory mouse strains.","date":"2012","source":"Genome biology","url":"https://pubmed.ncbi.nlm.nih.gov/22524474","citation_count":135,"is_preprint":false},{"pmid":"11123678","id":"PMC_11123678","title":"Evidence for the secretion of Chlamydia trachomatis CopN by a type III secretion mechanism.","date":"2000","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/11123678","citation_count":132,"is_preprint":false},{"pmid":"31173893","id":"PMC_31173893","title":"Phosphatidylinositol synthesis at the endoplasmic reticulum.","date":"2019","source":"Biochimica et biophysica acta. 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its existence was inferred from EST database screening alongside CDS1, with both enzymes localized to the ER and their overexpression shown not to be rate-limiting for cellular phosphatidylinositol content.\",\n      \"method\": \"cDNA cloning from EST database, expression in COS-7 cells, in vitro enzyme activity assay, Northern blot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro enzymatic activity demonstrated, functional expression in mammalian cells, replicated by independent cloning papers\",\n      \"pmids\": [\"9407135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Human CDS2 gene was cloned, sequenced, and mapped to chromosome 20p13 by radiation hybrid panel mapping and FISH; the encoded protein is homologous to Drosophila CDP-diacylglycerol synthase required for phototransduction.\",\n      \"method\": \"cDNA cloning, radiation hybrid mapping, fluorescence in situ hybridization (FISH)\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct chromosomal mapping with two independent methods in a peer-reviewed study\",\n      \"pmids\": [\"9806839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"CDS2 full-length cDNA was isolated and shown to encode a protein 64.4% identical to Drosophila CDS; in situ hybridization showed Cds2 is highly expressed in differentiating neuroblasts of the neural retina and CNS during embryonic mouse development but absent from adult retina.\",\n      \"method\": \"cDNA isolation, sequence analysis, RNA in situ hybridization on mouse tissue sections\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization by in situ hybridization with developmental context established\",\n      \"pmids\": [\"9889000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"PPARα activation in mouse heart in vivo upregulates CDS-2 activity and mRNA levels and stimulates cardiolipin de novo biosynthesis; this regulation was absent in PPARα-null mice, placing CDS2 downstream of PPARα in cardiac cardiolipin synthesis.\",\n      \"method\": \"Clofibrate treatment of wild-type and PPARα-null mice, CDS-2 enzyme activity assay, mRNA quantification, cardiolipin biosynthesis assay\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis using knockout mice plus enzyme activity assays in multiple model systems\",\n      \"pmids\": [\"14594999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Murine Cds2 (and Cds1) proteins were shown by transient transfection with epitope-tagged constructs to localize to the endoplasmic reticulum; Cds2 exhibits ubiquitous expression while Cds1 is restricted, and the two proteins are 73% identical.\",\n      \"method\": \"Fluorescence microscopy of epitope-tagged proteins in transiently transfected cells, RT-PCR expression analysis, FISH chromosomal mapping\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — subcellular localization by overexpressed tagged protein without functional consequence demonstrated\",\n      \"pmids\": [\"16023307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CDS-2 shRNA knockdown in HepG2/HEK293T cells disrupted cardiolipin biosynthesis and abolished mitomycin C-induced mitochondrial translocation of p53, demonstrating that CDS2-dependent cardiolipin synthesis is required for p53 mitochondrial localization and its downstream regulation of Bcl-xL and Bcl-2.\",\n      \"method\": \"shRNA knockdown, immunoblot fractionation of mitochondria, cardiolipin biosynthesis disruption assay\",\n      \"journal\": \"Neoplasia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with specific organellar fractionation readout; single study\",\n      \"pmids\": [\"20126473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In FATP-1-overexpressing HEK293 cells, CDS-2 mRNA expression and CDS enzyme activity were reduced, correlating with decreased cardiolipin synthesis; in vitro CDS activity was inhibited by exogenous oleoyl-CoA, suggesting FATP-1 regulates cardiolipin biosynthesis through CDS-2.\",\n      \"method\": \"siRNA knockdown and overexpression of FATP-1, CDS enzyme activity assay, mRNA quantification, radiolabeled glycerol incorporation into cardiolipin, in vitro CDS activity with oleoyl-CoA\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro enzyme inhibition assay plus cell-based knockdown/overexpression; single lab\",\n      \"pmids\": [\"19523918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CDS1 and CDS2 are integral membrane proteins of the ER, while the mitochondrial CDP-diacylglycerol synthase activity previously attributed to CDS1 was traced to the peripheral mitochondrial protein TAMM41; TAMM41 knockdown reduced mitochondrial CDS activity, cardiolipin levels, and oxygen consumption.\",\n      \"method\": \"Subcellular fractionation, immunoblot, siRNA knockdown of TAMM41, cardiolipin quantification, oxygen consumption measurement, differentiation of H9c2 cells\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular and cell biology of lipids\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods distinguishing ER vs. mitochondrial localization with functional readout; strong mechanistic insight\",\n      \"pmids\": [\"29253589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Knockdown of CDS2 (or CDS1) in cultured mammalian cells causes formation of giant/supersized lipid droplets and increases phosphatidic acid levels in the ER; CDS2 depletion had a moderate inhibitory effect on 3T3-L1 adipocyte differentiation.\",\n      \"method\": \"siRNA knockdown, fluorescence microscopy of lipid droplets, lipidomic analysis of PA species, 3T3-L1 differentiation assay\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean knockdown with defined cellular phenotype and lipidomic mechanistic readout; replicated in follow-up study\",\n      \"pmids\": [\"26946540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"p53 physically interacts with SIRT6 in vitro and in vivo, and the complex binds promoters of CDS1 and CDS2 to enhance their transcription; SIRT6 acts as a co-activator recruiting RNA polymerase II to CDS2 promoter, thereby regulating cardiolipin de novo biosynthesis.\",\n      \"method\": \"Co-immunoprecipitation (in vitro and in vivo), chromatin immunoprecipitation (ChIP), reporter assays, palmitic acid treatment\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus ChIP establishing direct transcriptional regulation; single lab\",\n      \"pmids\": [\"30237540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Genetic ablation of CDS2 in zebrafish and mouse endothelium switches VEGFA signaling from pro-angiogenic to pro-regressive; mechanistically, VEGFA stimulation in CDS2-null endothelium reduces PIP2 availability, causing PIP3 deficiency and FOXO1 activation that triggers vessel regression.\",\n      \"method\": \"Zebrafish cds2 mutant live imaging, conditional mouse CDS2 knockout (retina and tumor models), PIP2/PIP3 measurements, FOXO1 activation assay\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple model systems (zebrafish, mouse retina, tumor), live imaging, and defined signaling pathway established\",\n      \"pmids\": [\"31501519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CDS2, but not CDS1, contributes to increased PI resynthesis during PLC activation; CDS2 preferentially routes arachidonoyl-enriched PA species toward PI synthesis, contributing to maintenance of the 38:4 fatty acid profile of phosphoinositides during agonist stimulation.\",\n      \"method\": \"Stable isotope labeling (13C-glucose), mass spectrometry of PI species, siRNA knockdown of CDS2 vs CDS1, agonist-stimulated PLC assays\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — stable isotope tracing with mass spectrometry plus specific gene knockdowns distinguishing CDS1 vs CDS2 roles\",\n      \"pmids\": [\"35712788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CDS2 deficiency (but not CDS1 deficiency) promotes LD association of DGAT2 and GPAT4 and impairs initial LD maturation; reducing DGAT2 or GPAT4 expression rescued the giant LD phenotype in CDS2-deficient cells but not CDS1-deficient cells, revealing distinct mechanisms for CDS1 vs CDS2 in LD growth.\",\n      \"method\": \"siRNA knockdown, CRISPR/Cas9 knockout, fluorescence microscopy, immunological localization of DGAT2/GPAT4 at LDs\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR KO plus epistasis (double knockdown rescue) distinguishing molecular mechanisms; replicated across two labs\",\n      \"pmids\": [\"31548309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Liver-specific CDS2 deficiency in mice caused hepatic steatosis, inflammation, and fibrosis; CDS2 is enriched in mitochondria-associated membranes (MAMs) and its loss impairs mitochondrial function and decreases mitochondrial PE levels; overexpression of PISD (phosphatidylserine decarboxylase) rescued the NASH-like phenotype, placing CDS2 upstream of mitochondrial PE synthesis.\",\n      \"method\": \"Liver-specific Cds2 knockout mice, MAM fractionation, mitochondrial function assays, lipidomics, PISD overexpression rescue, PPARα agonist treatment\",\n      \"journal\": \"Science bulletin\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO mouse model with organellar fractionation, lipidomics, and genetic rescue establishing pathway position\",\n      \"pmids\": [\"36546079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In primary mouse macrophages, CDS2 deletion causes modest changes in steady-state PI but substantially increases PA, CDP-DG, DG, and TG; stable isotope labeling showed CDS2 loss minimally reduces de novo PI synthesis rate but substantially increases de novo PA synthesis from G3P. Under sustained PLC stimulation, CDS2-deficient macrophages cannot maintain enhanced PI synthesis ('PI cycle'), causing PI depletion; CDS2 deficiency also causes calcium homeostasis defects independent of PLC activation.\",\n      \"method\": \"CRISPR/Cas9 knockout in primary macrophages, stable isotope labeling (13C6-glucose, 13C6D7-glucose), lipidomics, GPCR-stimulated PLC assays, calcium imaging\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — stable isotope tracing plus KO in primary cells with multiple orthogonal readouts; single but rigorous study\",\n      \"pmids\": [\"39312194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CDS2 is a synthetic lethal target in the context of low CDS1 expression in uveal melanoma and multiple tumor types; CDS2 knockout disrupts phosphoinositide synthesis and increases cellular apoptosis; re-expression of CDS1 rescues the cell fitness defect; synthetic lethality depends on CDS2 catalytic activity and operates in vivo.\",\n      \"method\": \"Genome-wide CRISPR-Cas9 single and paired-gene screens in 10 uveal melanoma cell lines, CDS1 re-expression rescue, in vivo tumor models, pan-cancer data analysis\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genome-scale CRISPR screen plus mechanistic rescue experiments in multiple cell lines and in vivo models; two independent papers in the same journal issue\",\n      \"pmids\": [\"40615675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CDS2 essentiality in mesenchymal-like (CDS1-low) cancers is accompanied by disruption of lipid homeostasis including accumulation of cholesterol esters and triglycerides; synthetic lethality is driven by CDS2 dosage and requires catalytic activity; no common CRISPR escape mechanism was identified, indicating robustness of the interaction.\",\n      \"method\": \"Genome-wide CRISPR-Cas9 KO screens in CDS1-negative cancer cells, lipidomics, catalytic mutant rescue experiments\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — catalytic mutant rescue plus genome-wide screen and lipidomics; independent replication of CDS1/CDS2 SLI in companion paper\",\n      \"pmids\": [\"40615674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Under physiological conditions MBOAT7 interacts with CDS2 at the ER to maintain lipid metabolic homeostasis; CDS2 knockdown or loss of function triggers MBOAT7 translocation from ER to ER-LD contact sites in a RAB1-dependent manner, where it inhibits DGAT2-mediated LD growth and promotes lipolysis.\",\n      \"method\": \"Co-immunoprecipitation, fluorescence microscopy of MBOAT7 localization, CDS2 knockdown, RAB1 dependency assay, LD size measurement, lipolysis assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus live-cell localization and functional rescue; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.08.26.672501\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"CDS2 is an integral ER membrane enzyme that converts phosphatidic acid to CDP-diacylglycerol, serving as the rate-limiting step for phosphatidylinositol (PI) resynthesis during PLC signaling—particularly for arachidonoyl-enriched PI species—and is a synthetic lethal partner with its paralog CDS1, such that CDS2 loss in CDS1-low contexts disrupts phosphoinositide homeostasis, elevates PA/DG/TG, triggers apoptosis, promotes giant lipid droplet formation via DGAT2/GPAT4 recruitment, and in endothelial cells causes VEGFA-driven vessel regression through PIP2/PIP3 depletion and FOXO1 activation; its expression is regulated transcriptionally by p53-SIRT6 and PPARα, and it localizes to mitochondria-associated membranes where it supports mitochondrial PE levels and function.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CDS2 is an integral endoplasmic reticulum membrane enzyme that catalyzes the conversion of phosphatidic acid (PA) to CDP-diacylglycerol (CDP-DAG), serving as the committed step for phosphatidylinositol (PI) resynthesis during phospholipase C signaling. CDS2 preferentially channels arachidonoyl-enriched PA species toward PI synthesis and is specifically required to sustain the PI cycle during agonist-stimulated PLC activation; its loss causes PA, diacylglycerol, and triglyceride accumulation, giant lipid droplet formation via DGAT2/GPAT4 recruitment, and calcium homeostasis defects [PMID:35712788, PMID:39312194, PMID:31548309, PMID:26946540]. CDS2 localizes to mitochondria-associated membranes where it supports mitochondrial phosphatidylethanolamine levels, and liver-specific CDS2 deletion causes hepatic steatosis, inflammation, and fibrosis [PMID:36546079]. CDS2 is a robust synthetic lethal partner of its paralog CDS1, such that CDS2 loss in CDS1-low cancers disrupts phosphoinositide homeostasis and triggers apoptosis in a catalytic-activity-dependent manner [PMID:40615675, PMID:40615674].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Identification of CDS2 as a second mammalian CDP-diacylglycerol synthase established that PA-to-CDP-DAG conversion is catalyzed by two distinct isoforms, raising the question of whether they serve redundant or specialized roles.\",\n      \"evidence\": \"cDNA cloning from EST database, expression in COS-7 cells with in vitro enzyme activity assay\",\n      \"pmids\": [\"9407135\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No isoform-specific substrates or regulation identified\", \"Overexpression did not limit PI content, leaving physiological rate-limiting role unclear\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstration that PPARα activates CDS2 transcription and CDS2-dependent cardiolipin biosynthesis in heart tissue established the first transcriptional regulator of CDS2 and linked it to cardiac mitochondrial lipid metabolism.\",\n      \"evidence\": \"Clofibrate treatment of wild-type vs. PPARα-null mice with CDS-2 enzyme activity and mRNA quantification\",\n      \"pmids\": [\"14594999\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PPARα directly binds CDS2 promoter or acts indirectly was not resolved\", \"Cardiac-specific role versus systemic relevance unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"CDS2 knockdown disrupted cardiolipin biosynthesis and abolished mitomycin C-induced p53 mitochondrial translocation, revealing CDS2 as required for a stress-activated apoptotic signaling step.\",\n      \"evidence\": \"shRNA knockdown in HepG2/HEK293T cells with mitochondrial fractionation and immunoblot\",\n      \"pmids\": [\"20126473\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single study without independent replication\", \"Whether cardiolipin itself or downstream lipid changes mediate p53 translocation was not distinguished\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"CDS2 depletion was shown to cause giant lipid droplet formation and ER phosphatidic acid accumulation, establishing that CDS2 controls PA flux away from neutral lipid storage pathways.\",\n      \"evidence\": \"siRNA knockdown with fluorescence microscopy and lipidomic analysis of PA species\",\n      \"pmids\": [\"26946540\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which elevated PA drives giant LD formation not yet defined\", \"CDS1 vs CDS2 specificity in LD phenotype not resolved in this study\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Definitive ER localization of CDS1/CDS2 was established by showing that mitochondrial CDP-DAG synthase activity belongs to TAMM41, not CDS2, resolving a longstanding compartmental ambiguity.\",\n      \"evidence\": \"Subcellular fractionation, siRNA knockdown of TAMM41, cardiolipin and oxygen consumption measurements in H9c2 cells\",\n      \"pmids\": [\"29253589\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address CDS2 presence at mitochondria-associated membranes (later shown)\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The p53–SIRT6 complex was shown to directly bind CDS2 promoter and recruit RNA polymerase II, identifying a second transcriptional axis controlling CDS2 expression relevant to cardiolipin metabolism.\",\n      \"evidence\": \"Co-immunoprecipitation and chromatin immunoprecipitation with reporter assays\",\n      \"pmids\": [\"30237540\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single laboratory study\", \"Physiological contexts beyond palmitate stress not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Two key advances distinguished CDS2 from CDS1: (1) CDS2 specifically sustains PI resynthesis during PLC signaling by preferentially routing arachidonoyl-PA toward PI, and (2) CDS2 loss uniquely promotes DGAT2/GPAT4 recruitment to lipid droplets, a phenotype rescued by depleting these enzymes.\",\n      \"evidence\": \"Stable isotope tracing with mass spectrometry for PI species (CDS2 vs CDS1 knockdown); CRISPR KO plus double-knockdown rescue of giant LD phenotype\",\n      \"pmids\": [\"35712788\", \"31548309\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for CDS2 substrate selectivity toward arachidonoyl-PA unknown\", \"Mechanism linking local PA to DGAT2/GPAT4 recruitment not fully defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Genetic ablation of CDS2 in zebrafish and mouse endothelium converted VEGFA signaling from pro-angiogenic to pro-regressive through PIP2/PIP3 depletion and FOXO1 activation, revealing CDS2 as a vascular-specific gatekeeper of PI-dependent signaling.\",\n      \"evidence\": \"Zebrafish cds2 mutant live imaging, conditional mouse CDS2 KO in retinal and tumor vasculature, PIP2/PIP3 measurement\",\n      \"pmids\": [\"31501519\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other PI-dependent pathways (e.g., mTOR) are similarly affected in endothelium not tested\", \"Contribution of CDS1 compensation in vivo not quantified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Liver-specific CDS2 deletion caused NASH-like pathology; CDS2 enrichment at mitochondria-associated membranes and rescue by PISD overexpression placed CDS2 upstream of mitochondrial PE synthesis, linking ER CDP-DAG production to mitochondrial membrane lipid homeostasis.\",\n      \"evidence\": \"Liver-specific Cds2 KO mice, MAM fractionation, lipidomics, PISD genetic rescue\",\n      \"pmids\": [\"36546079\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CDP-DAG generated at ER/MAMs feeds into mitochondrial PE synthesis pathway is mechanistically unclear\", \"Whether CDS1 compensates in other tissues not addressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Isotope tracing in primary CDS2-KO macrophages showed that CDS2 is dispensable for basal PI synthesis rates but essential to sustain enhanced PI resynthesis during PLC stimulation, and revealed CDS2 loss causes calcium dysregulation independent of PLC.\",\n      \"evidence\": \"CRISPR KO in primary macrophages, dual stable isotope labeling, GPCR-stimulated PLC assays, calcium imaging\",\n      \"pmids\": [\"39312194\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of PLC-independent calcium defect not identified\", \"Whether findings extend to non-macrophage immune cells unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Two independent genome-wide CRISPR screens identified CDS2 as a robust synthetic lethal target in CDS1-low cancers; the interaction depends on CDS2 catalytic activity, operates in vivo, and is accompanied by broad lipid homeostasis disruption including cholesterol ester and triglyceride accumulation.\",\n      \"evidence\": \"Genome-wide CRISPR screens across uveal melanoma and pan-cancer cell lines, catalytic mutant rescue, CDS1 re-expression rescue, in vivo tumor models, lipidomics\",\n      \"pmids\": [\"40615675\", \"40615674\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No therapeutic agent targeting CDS2 yet developed\", \"Mechanisms of downstream apoptosis induction beyond lipid imbalance not fully delineated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis for CDS2's preference for arachidonoyl-PA substrates, the mechanism by which CDS2-derived CDP-DAG at MAMs supports mitochondrial PE, and whether CDS2 inhibition can be therapeutically exploited in CDS1-low cancers remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No crystal or cryo-EM structure of CDS2\", \"No small-molecule CDS2 inhibitor reported\", \"Precise lipid transfer mechanism from ER/MAM CDP-DAG pool to mitochondrial PE synthesis unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 11, 14, 15, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 4, 7, 8]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"GO:0005811\", \"supporting_discovery_ids\": [8, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 3, 8, 11, 13, 14]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [10, 11, 14]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [5, 15]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CDS1\",\n      \"DGAT2\",\n      \"GPAT4\",\n      \"MBOAT7\",\n      \"SIRT6\",\n      \"TP53\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}