{"gene":"DLAT","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2021,"finding":"Dlat (dihydrolipoamide S-acetyltransferase) was identified as a direct molecular target of the phytochemical hyperforin (HPF) using LiP-SMap (limited proteolysis-mass spectrometry), microscale thermophoresis, and molecular docking. Ablation of Dlat significantly attenuated HPF-mediated adipose tissue browning both in vitro and in vivo, placing Dlat upstream of AMPK and PGC-1α in a thermogenic pathway.","method":"LiP-SMap, microscale thermophoresis, molecular docking, Dlat knockout/ablation with thermogenesis phenotype readout","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal biochemical methods (LiP-SMap, MST, docking) plus genetic loss-of-function in vitro and in vivo confirming functional consequence","pmids":["33657393"],"is_preprint":false},{"year":2024,"finding":"Dlat interacts with transient receptor potential vanilloid 3 (Trpv3) to activate the calcium channel, increasing intracellular Ca2+ and activating CaMKKβ, which then stimulates AMPK to elevate Ucp1 expression and initiate adipose thermogenesis. HPF promotes thermogenesis by enhancing the Dlat-Trpv3 interaction independently of β3-adrenergic receptor signaling; thermogenic effects were reduced in Dlat+/- mice.","method":"Co-immunoprecipitation/interaction assays, Seahorse assays, JC-1 staining, qPCR, immunoblotting, Dlat heterozygous knockout mice on HFD","journal":"Journal of advanced research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function in vivo plus interaction assays and multiple functional readouts, single lab","pmids":["39631519"],"is_preprint":false},{"year":2011,"finding":"PDC-E2 (DLAT) is constitutively present in the nucleus of BaF3 cells and functions as a co-activator of STAT5-dependent gene transcription. Nuclear PDC-E2 is lipoylated and associates with PDC-E1; IL-3-induced phosphorylated STAT5 co-immunoprecipitates with nuclear PDC-E2. PDC-E2 overexpression augments STAT5-driven reporter activity and elevates endogenous SOCS3 mRNA levels.","method":"Subcellular fractionation, co-immunoprecipitation, confocal immunofluorescence, reporter assay, qRT-PCR","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (fractionation, Co-IP, confocal, reporter assay), single lab","pmids":["21397011"],"is_preprint":false},{"year":2025,"finding":"DLAT directly acetylates AU RNA-binding methylglutaconyl-CoA hydratase (AUH) at lysine 109 (K109), inhibiting its activity and causing leucine accumulation that sustains mTOR complex activation in hepatocellular carcinoma. This reveals an unexpected acetyltransferase function of DLAT beyond its canonical role in the pyruvate dehydrogenase complex.","method":"Direct acetylation assay (in vitro), site-directed mutation of AUH K109, mass spectrometry identification of acetylation site, mTOR activity readout, xenograft models with AUHK109R-mRNA LNP rescue","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic assay with mutagenesis (K109R) plus in vivo rescue experiment, multiple orthogonal methods in single rigorous study","pmids":["40112809"],"is_preprint":false},{"year":2025,"finding":"Mitochondrial lysine methyltransferase KMT9 monomethylates DLAT at lysine 596 (K596me1) to regulate pyruvate dehydrogenase complex (PDC) activity. KMT9 depletion compromises PDC activity, de novo lipogenesis, and prostate cancer cell proliferation in vitro and in a mouse model. KMT9 localizes to mitochondria specifically in prostate cancer cells.","method":"Mass spectrometry identification of K596me1, KMT9 depletion (in vitro and in vivo mouse model), PDC activity assay, de novo lipogenesis assay, mitochondrial fractionation/localization","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — PTM identified by MS with functional validation via KO in vitro and in vivo, multiple orthogonal methods in single rigorous study","pmids":["39885202"],"is_preprint":false},{"year":2026,"finding":"DLAT directly binds to the mitochondrial glutathione transporter SLC25A39 and enhances its protein stability independent of intracellular GSH levels, maintaining mitochondrial GSH import and redox homeostasis. Knockdown of DLAT or SLC25A39 disrupts mtGSH transport, elevates lipid peroxidation, and sensitizes colorectal cancer cells to ferroptosis.","method":"Co-immunoprecipitation (direct binding), siRNA knockdown with ferroptosis phenotype readout (lipid peroxidation, mtGSH measurement), protein stability assay","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding demonstrated by Co-IP plus loss-of-function with specific molecular phenotype, single lab","pmids":["42009144"],"is_preprint":false},{"year":2024,"finding":"p32 (C1QBP) directly interacts with DLAT in the mitochondria, and increasing p32 expression increases oxidative phosphorylation by interacting with DLAT to regulate pyruvate dehydrogenase complex (PDHc) activation. p32 has direct binding affinity for copper and facilitates copper-induced oligomerization of lipoylated DLAT (lipo-DLAT) specifically in clear cell renal cell carcinoma (ccRCC) cells.","method":"Co-immunoprecipitation (p32-DLAT), copper binding assay, DLAT oligomerization assay, Seahorse assay (OXPHOS), animal models","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus multiple functional assays, single lab","pmids":["38169635"],"is_preprint":false},{"year":2023,"finding":"MELK activates PI3K/mTOR signaling to upregulate DLAT expression and stabilize mitochondrial function in hepatocellular carcinoma. Elevated DLAT (particularly the monomeric form) promotes elesclomol drug resistance and reduces cuproptosis susceptibility. Elesclomol treatment reduced TOM20 expression and increased DLAT oligomers, and MELK-mediated effects were abolished by elesclomol treatment.","method":"siRNA knockdown, DLAT overexpression, Western blotting (DLAT monomer vs. oligomer), PI3K/mTOR pathway inhibition, xenograft models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss/gain-of-function with pathway inhibition, multiple cellular and in vivo readouts, single lab","pmids":["37949877"],"is_preprint":false},{"year":2023,"finding":"DLAT functions as a cuproptosis promoter in hepatocellular carcinoma; siRNA-mediated downregulation of DLAT effectively inhibited copper ionophore (elesclomol)-induced cuproptosis in a copper-dependent manner. Selective Cu2+ chelation with ammonium tetrathiomolybdate also inhibited cuproptosis.","method":"siRNA loss-of-function, CCK8 cell viability assay, Western blotting (DLAT expression), elesclomol-copper cuproptosis induction","journal":"Current medical science","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — loss-of-function with specific cell death phenotype, single lab, single main method","pmids":["37286711"],"is_preprint":false},{"year":2023,"finding":"Cuproptosis-upregulated DLAT inhibits autophagy, promotes G2/M phase cell cycle retention, and enhances docetaxel chemosensitivity in prostate cancer via the mTOR signaling pathway. These effects were demonstrated both in vitro and in xenograft models.","method":"Elesclomol-CuCl2 treatment, Western blotting, cell cycle flow cytometry, transmission electron microscopy, mTOR signaling analysis, xenograft model","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (flow cytometry, TEM, signaling pathway analysis, in vivo), single lab","pmids":["37584654"],"is_preprint":false},{"year":2022,"finding":"PM2.5 upregulates DLAT expression through two mechanisms: (1) activating eIF4E to increase DLAT translation (shown by polysome fractionation), and (2) stimulating transcription factor Sp1 to augment DLAT promoter transcriptional activity (shown by ChIP and dual-luciferase reporter assay). Elevated DLAT promotes glycolysis but suppresses acetyl-CoA production, enhancing NSCLC malignancy.","method":"Polysome fractionation (Ribo-seq), ChIP, dual-luciferase reporter assay, Seahorse XF glycolysis stress assay, gain/loss-of-function experiments","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two distinct mechanistic pathways each supported by orthogonal methods, single lab","pmids":["35869499"],"is_preprint":false},{"year":2025,"finding":"DLAT enhances glucose transporter 1 (GLUT1) expression via H3K18 acetylation, promoting aerobic glycolysis and epithelial-to-mesenchymal transition (EMT) to augment HCC metastasis. Functional cytology experiments confirmed that DLAT drives tumor metastasis by driving metabolic reprogramming.","method":"RNA sequencing, tissue microarrays, in vitro and in vivo functional assays, H3K18 acetylation analysis, Western blot","journal":"Molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — H3K18 acetylation mechanistic link supported by in vitro and in vivo experiments, single lab","pmids":["39979835"],"is_preprint":false},{"year":2021,"finding":"PDC-E2 (DLAT) interacts with phosphorylated STAT3 (pY-STAT3) under cholestatic conditions in human cholangiocytes (NHC). GCDC treatment induced PDC-E2 expression and stimulated pY-STAT3 phosphorylation; siRNA silencing of PDC-E2 reduced pY-STAT3 expression specifically in NHC. Immunoprecipitation and proximity ligation assay confirmed GCDC-enhanced pY-STAT3 binding to PDC-E2 in nuclear and cytoplasmic fractions. PDC-E2/pS-STAT3 complexes were also detected in mitochondria.","method":"Co-immunoprecipitation, proximity ligation assay, siRNA knockdown, subcellular fractionation, MitoTracker co-localization","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction confirmed by two orthogonal methods (Co-IP and PLA), siRNA functional validation, single lab","pmids":["34737337"],"is_preprint":false},{"year":2024,"finding":"DLAT directly interacts with YAP1, leading to dephosphorylation and activation of YAP1 and increased nuclear translocation, thereby transcriptionally activating downstream oncogenes and promoting the malignant phenotype of triple-negative breast cancer. Rescue experiments confirmed that DLAT promotes malignant behavior through a YAP1-dependent pathway.","method":"Co-immunoprecipitation, cytoplasmic-nuclear separation experiments, Western blot, rescue experiments with YAP1 manipulation","journal":"Cancer biology & therapy","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP plus nuclear translocation assay and rescue experiments, single lab","pmids":["39460738"],"is_preprint":false},{"year":2025,"finding":"DLAT directly binds to CASP3 and CASP9 proteins in granulosa cells to inhibit apoptosis, and DLAT overexpression increased PCNA and MCL1 levels to promote granulosa cell proliferation. Pyruvate upregulates DLAT expression, and high DLAT levels in large follicles promote follicular growth.","method":"Protein binding assay (DLAT-CASP3/CASP9), qRT-PCR, Western blot, cell proliferation assay, in vivo follicular growth experiments","journal":"Cells","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, binding shown but method not fully specified in abstract, limited mechanistic depth","pmids":["40136693"],"is_preprint":false},{"year":2026,"finding":"Dlat acts as a key transacetylase for mitochondrial protein hyperacetylation in HFpEF hearts. Dlat directly acetylates the alpha subunit of mitochondrial trifunctional protein (HADHA) at K728, inactivating HADHA enzymatic activity and inhibiting fatty acid oxidation. Dlat overexpression enhanced FAO-related protein acetylation and exacerbated cardiac lipid metabolism disturbances; Dlat knockdown mitigated FAO inhibition and HFpEF phenotypes.","method":"In vitro acetylation assay (Dlat→HADHA K728), site-specific acetylation identification by MS, Dlat KO/OE with FAO and cardiac function readouts","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic acetylation with identified substrate site, genetic loss/gain-of-function in vivo with specific metabolic and cardiac phenotype readouts","pmids":["41826295"],"is_preprint":false},{"year":2025,"finding":"DLAT promotes lipid metabolism reprogramming in ovarian cancer via the JAK2/STAT5/SREBP1 signaling axis. DLAT silencing reduced lipid content and impaired OC cell proliferation, migration, and invasion. DLAT upregulated SREBP1 expression through JAK2/STAT5 signaling, enhancing fatty acid synthesis; SREBP1 was essential for DLAT-dependent OC cell growth and metastasis in vitro and in vivo.","method":"siRNA knockdown, Western blot (JAK2/STAT5/SREBP1 pathway), lipid detection assays, SREBP1 overexpression rescue, xenograft mouse model","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway placement by rescue experiment plus in vivo model, multiple methods, single lab","pmids":["39871246"],"is_preprint":false},{"year":2024,"finding":"Microglial exosomes facilitate transfer of PKM2 to neurons, leading to upregulation of DLAT expression and increased copper-induced neuronal death in Alzheimer's disease context. Inhibition of PKM2 transfer via exosomes resulted in significant reduction in DLAT expression, mitigating neuronal death. DLAT was validated as increased in 5xFAD transgenic mice hippocampus.","method":"In vitro exosome transfer assay, PKM2 inhibition, siRNA/knockdown of PKM2 transfer, 5xFAD transgenic mouse model, Western blot","journal":"CNS neuroscience & therapeutics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mechanistic pathway inferred from exosome transfer experiments with limited direct evidence for DLAT-specific mechanism, single lab","pmids":["39428563"],"is_preprint":false},{"year":1993,"finding":"Lipoylation of the lysine residue in the inner lipoyl domain of human PDC-E2 is crucial for effective autoantibody recognition in primary biliary cirrhosis. Purified lipoylated and unlipoylated forms of the inner lipoyl domain were compared in immunoblotting, ELISA inhibition experiments, and antibody affinity measurements; PBC autoantibodies have higher relative affinity for the lipoylated form, recognizing a unique peptide-cofactor conformation.","method":"Recombinant protein expression in E. coli, affinity purification of lipoylated/unlipoylated forms, ELISA inhibition, immunoblotting, affinity measurements","journal":"Hepatology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — reconstituted recombinant protein forms with multiple biochemical assays, single lab","pmids":["7694896"],"is_preprint":false},{"year":1990,"finding":"Site-directed mutagenesis of the lysine residue in the lipoyl domain of human PDC-E2 (replacing lysine with glutamine, histidine, or tyrosine) demonstrated that the recognition of the immunodominant autoepitope by PBC patient sera is dependent on the lipoyl domain structure rather than simply the charge or chemistry of the lysine sidechain alone; the recognition reflects the surface-exposed, hydrophilic, mobile nature of the lipoyl domain region.","method":"Oligonucleotide-directed site-directed mutagenesis, ELISA, immunoblotting, specific absorption assays with patient sera","journal":"Hepatology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro mutagenesis with functional autoantibody recognition assays, single lab","pmids":["1701753"],"is_preprint":false},{"year":2015,"finding":"siRNA-mediated knockdown of DLAT in gastric cancer cell lines supported a role for DLAT in cell proliferation and carbohydrate metabolism, consistent with its function as a subunit of the pyruvate dehydrogenase complex involved in metabolic reprogramming in cancer.","method":"siRNA knockdown, cell proliferation assay, metabolic assays","journal":"American journal of translational research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single knockdown experiment with phenotypic readout, no pathway placement, single lab","pmids":["26279757"],"is_preprint":false},{"year":1993,"finding":"PDC-E2 (DLAT) gene was mapped to human chromosome 11 band q23.1 using fluorescence in situ hybridization, and a TaqI restriction fragment length polymorphism was identified. The chromosomal location was experimentally determined.","method":"Fluorescence in situ hybridization (FISH), RFLP analysis with restriction enzymes","journal":"Autoimmunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct FISH localization experiment, single lab but established chromosomal position","pmids":["8102256"],"is_preprint":false},{"year":2026,"finding":"NAT10 enhances DLAT mRNA stability by mediating its N4-acetylcytidine (ac4C) modification, promoting DLAT expression and cuproptosis in colorectal cancer. Lactylation of NAT10 at K426 enhances NAT10 catalytic activity, while SIRT1-mediated delactylation of NAT10-K426 inhibits cuproptosis. Elesclomol-induced reduction of soluble DLAT feeds back to enhance NAT10-K426 lactylation, creating a positive feedback loop.","method":"ac4C RNA modification assay, NAT10 knockdown/overexpression, SIRT1 inhibition (selisistat), DLAT mRNA stability assay, lactylation site identification (K426)","journal":"Proceedings of the National Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA modification mechanism with post-translational modification of regulator identified, multiple functional experiments, single lab","pmids":["42085165"],"is_preprint":false}],"current_model":"DLAT (PDC-E2/dihydrolipoamide S-acetyltransferase) is the E2 subunit of the mitochondrial pyruvate dehydrogenase complex whose lipoylated form is the immunodominant autoantigen in primary biliary cholangitis; beyond its canonical metabolic role, DLAT functions as a non-canonical acetyltransferase targeting substrates including AUH (K109) and HADHA (K728) to suppress leucine catabolism and fatty acid oxidation respectively, undergoes KMT9-mediated monomethylation at K596 to regulate PDC activity, localizes to the nucleus where it co-activates STAT5-dependent transcription, interacts with Trpv3 to activate calcium-AMPK-UCP1 thermogenic signaling, and serves as the key copper-binding lipoylated protein whose oligomerization drives cuproptosis downstream of FDX1-mediated lipoic acid reduction."},"narrative":{"mechanistic_narrative":"DLAT (PDC-E2/dihydrolipoamide S-acetyltransferase) is the lipoylated E2 core subunit of the mitochondrial pyruvate dehydrogenase complex, and its activity is tuned by post-translational modification: KMT9 monomethylates DLAT at K596 to sustain PDC activity, de novo lipogenesis, and prostate cancer proliferation [PMID:39885202]. Beyond catalysis, DLAT has emerged as a non-canonical acetyltransferase that directly acetylates substrate lysines to reprogram metabolism — it acetylates AUH at K109 to inhibit leucine catabolism and sustain mTOR activation in hepatocellular carcinoma [PMID:40112809], and acetylates the trifunctional protein subunit HADHA at K728 to inactivate fatty acid oxidation in HFpEF hearts [PMID:41826295]; it also drives GLUT1 expression through H3K18 acetylation to promote glycolysis and EMT in HCC [PMID:39979835]. DLAT is the key copper-binding lipoylated protein of cuproptosis: copper-driven oligomerization of lipo-DLAT executes copper ionophore–induced cell death, with the monomeric versus oligomeric balance determining cuproptosis susceptibility and drug resistance, and p32/C1QBP binding facilitating copper-induced oligomerization [PMID:38169635, PMID:37949877, PMID:37286711]. Its abundance is controlled transcriptionally (Sp1), translationally (eIF4E), and through NAT10-mediated ac4C mRNA stabilization, with elesclomol-driven depletion of soluble DLAT feeding a NAT10 lactylation feedback loop [PMID:35869499, PMID:42085165]. DLAT additionally localizes to the nucleus and to interaction partners that drive growth and metabolic signaling, including STAT5 co-activation [PMID:21397011], YAP1 dephosphorylation/activation [PMID:39460738], and a JAK2/STAT5/SREBP1 lipogenic axis [PMID:39871246], and engages thermogenic signaling by interacting with Trpv3 to activate a Ca2+–CaMKKβ–AMPK–UCP1 cascade in adipose browning [PMID:33657393, PMID:39631519]. The lipoylated inner lipoyl domain of DLAT is the immunodominant autoantigen recognized by primary biliary cholangitis autoantibodies, where lipoylation and the surface-exposed lipoyl domain conformation determine epitope recognition [PMID:7694896, PMID:1701753].","teleology":[{"year":1990,"claim":"Established that PBC autoantibody recognition of DLAT depends on the structure of its lipoyl domain rather than on the lysine sidechain chemistry alone, defining the molecular basis of the immunodominant autoepitope.","evidence":"Site-directed mutagenesis of the lipoyl-domain lysine with ELISA/immunoblot recognition by patient sera","pmids":["1701753"],"confidence":"Medium","gaps":["Did not establish how lipoylation status alters the surface conformation recognized","Single-lab in vitro system"]},{"year":1993,"claim":"Showed that lipoylation of the inner lipoyl-domain lysine is required for high-affinity autoantibody recognition, linking the metabolic cofactor to autoimmune antigenicity in PBC.","evidence":"Comparison of recombinant lipoylated vs unlipoylated lipoyl domains by ELISA inhibition, immunoblot, and affinity measurement","pmids":["7694896"],"confidence":"Medium","gaps":["Does not address why tolerance to this self-antigen is lost in disease","No structural model of the cofactor-peptide conformation"]},{"year":2011,"claim":"Revealed a non-mitochondrial role: nuclear DLAT acts as a STAT5 transcriptional co-activator, indicating functions beyond the PDC core.","evidence":"Subcellular fractionation, Co-IP with phospho-STAT5, confocal, and reporter/qRT-PCR in BaF3 cells","pmids":["21397011"],"confidence":"Medium","gaps":["Mechanism of DLAT nuclear import not defined","Whether lipoyltransferase activity is required for co-activation unknown"]},{"year":2021,"claim":"Identified DLAT as the direct target of hyperforin and placed it upstream of AMPK/PGC-1α in adipose thermogenesis, the first functional link of DLAT to a thermogenic pathway.","evidence":"LiP-SMap, microscale thermophoresis, docking, plus Dlat ablation with thermogenesis readout in vitro and in vivo","pmids":["33657393"],"confidence":"High","gaps":["Molecular effector downstream of DLAT not yet defined at this stage","Direct binding site of hyperforin not resolved"]},{"year":2022,"claim":"Defined how DLAT abundance is controlled, showing PM2.5 raises DLAT via Sp1 transcription and eIF4E translation, with elevated DLAT shifting NSCLC toward glycolysis.","evidence":"Polysome fractionation, ChIP, dual-luciferase reporter, Seahorse glycolysis assay with gain/loss-of-function","pmids":["35869499"],"confidence":"Medium","gaps":["How elevated DLAT suppresses acetyl-CoA production mechanistically unclear","Single-lab cell-based system"]},{"year":2023,"claim":"Established DLAT as the executor of cuproptosis, where copper-ionophore-induced death requires DLAT and depends on its monomer/oligomer state and upstream PI3K/mTOR-driven expression.","evidence":"siRNA loss-of-function, copper chelation, monomer vs oligomer Western blots, pathway inhibition, and xenografts across HCC and prostate cancer","pmids":["37286711","37949877","37584654"],"confidence":"Medium","gaps":["Structural basis of copper-induced lipo-DLAT oligomerization not resolved","Downstream death-execution steps after oligomerization undefined"]},{"year":2024,"claim":"Expanded DLAT interactomes linking it to thermogenesis, OXPHOS, and oncogenic signaling, including Trpv3-Ca2+-AMPK-UCP1, p32-facilitated copper oligomerization, and YAP1 activation.","evidence":"Co-IP/interaction assays, copper-binding and oligomerization assays, Seahorse, nuclear translocation, and rescue experiments across adipose, ccRCC, and TNBC models","pmids":["39631519","38169635","39460738"],"confidence":"Medium","gaps":["Whether these interactions are mitochondrial vs cytosolic/nuclear not always resolved","Direct binding interfaces not mapped"]},{"year":2025,"claim":"Defined the non-canonical acetyltransferase function of DLAT — direct acetylation of AUH at K109 — and a KMT9-mediated K596 monomethylation that regulates PDC activity, plus H3K18ac-driven GLUT1 induction and JAK2/STAT5/SREBP1 lipogenic reprogramming.","evidence":"In vitro acetylation assays with site mutagenesis (AUH K109R), MS PTM mapping (K596me1), KMT9 depletion, chromatin acetylation analysis, and in vivo rescue/xenograft models","pmids":["40112809","39885202","39979835","39871246"],"confidence":"High","gaps":["Catalytic mechanism of DLAT acting as a protein acetyltransferase not structurally defined","Full substrate repertoire and subcellular site of acetylation incompletely mapped"]},{"year":2026,"claim":"Showed DLAT-driven hyperacetylation inactivates fatty acid oxidation via HADHA-K728 acetylation, stabilizes mitochondrial GSH import through SLC25A39 binding, and is itself stabilized by NAT10-mediated ac4C in a cuproptosis feedback loop.","evidence":"In vitro acetylation with MS site identification, Co-IP/protein stability assays, ac4C modification and mRNA stability assays, with genetic perturbation and in vivo cardiac/CRC models","pmids":["41826295","42009144","42085165"],"confidence":"Medium","gaps":["How DLAT switches between catalytic, acetyltransferase, and copper-binding roles is unresolved","Mechanism balancing pro-cuproptotic vs ferroptosis-protective functions undefined"]},{"year":null,"claim":"The unifying biochemical basis by which a single mitochondrial PDC subunit performs metabolic catalysis, non-canonical protein/histone acetylation, copper-driven oligomerization, and nuclear transcriptional co-activation remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structure explaining moonlighting acetyltransferase activity","Determinants of DLAT subcellular partitioning between mitochondria and nucleus unknown","How PTMs (K596me1, lipoylation) gate these distinct activities not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[3,15,11]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3,15]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2,13,16]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[4,6,12,15]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,12,13]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[4,10,15,16]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[6,7,8,9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2,13,16]}],"complexes":["pyruvate dehydrogenase complex"],"partners":["TRPV3","STAT5","STAT3","YAP1","C1QBP","SLC25A39","CASP3","CASP9"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P10515","full_name":"Dihydrolipoyllysine-residue acetyltransferase component of pyruvate dehydrogenase complex, mitochondrial","aliases":["70 kDa mitochondrial autoantigen of primary biliary cirrhosis","PBC","Dihydrolipoamide acetyltransferase component of pyruvate dehydrogenase complex","M2 antigen complex 70 kDa subunit","Pyruvate dehydrogenase complex component E2","PDC-E2","PDCE2"],"length_aa":647,"mass_kda":69.0,"function":"The pyruvate dehydrogenase (PDH) complex, catalyzes the overall conversion of pyruvate to acetyl-CoA and CO(2), and thereby links cytoplasmic glycolysis and the mitochondrial tricarboxylic acid (TCA) cycle (Probable). It contains multiple copies of three enzymatic components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2) and dihydrolipoamide dehydrogenase (E3); (Probable). Within this complex, the catalytic function of this enzyme is to accept, and to transfer to coenzyme A, acetyl groups from acetyl-lipoyl moiety generated by the pyruvate dehydrogenase, leading to acetyl-CoA formation (Probable)","subcellular_location":"Mitochondrion matrix","url":"https://www.uniprot.org/uniprotkb/P10515/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DLAT","classification":"Not Classified","n_dependent_lines":12,"n_total_lines":1208,"dependency_fraction":0.009933774834437087},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAPZB","stoichiometry":0.2},{"gene":"CLIP1","stoichiometry":0.2},{"gene":"FKBP5","stoichiometry":0.2},{"gene":"HEATR3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/DLAT","total_profiled":1310},"omim":[{"mim_id":"616299","title":"LIPOYLTRANSFERASE 1 DEFICIENCY; LIPT1D","url":"https://www.omim.org/entry/616299"},{"mim_id":"610493","title":"DIX DOMAIN-CONTAINING PROTEIN 1; DIXDC1","url":"https://www.omim.org/entry/610493"},{"mim_id":"610284","title":"LIPOYLTRANSFERASE 1; LIPT1","url":"https://www.omim.org/entry/610284"},{"mim_id":"608770","title":"DIHYDROLIPOAMIDE S-ACETYLTRANSFERASE; DLAT","url":"https://www.omim.org/entry/608770"},{"mim_id":"604482","title":"SIRTUIN 4; SIRT4","url":"https://www.omim.org/entry/604482"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Mitochondria","reliability":"Supported"},{"location":"Connecting piece","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"tongue","ntpm":83.5}],"url":"https://www.proteinatlas.org/search/DLAT"},"hgnc":{"alias_symbol":["PDC-E2","E2"],"prev_symbol":["DLTA"]},"alphafold":{"accession":"P10515","domains":[{"cath_id":"2.40.50.100","chopping":"90-174","consensus_level":"high","plddt":83.0735,"start":90,"end":174},{"cath_id":"2.40.50.100","chopping":"217-301","consensus_level":"high","plddt":79.9707,"start":217,"end":301},{"cath_id":"3.30.559.10","chopping":"444-644","consensus_level":"high","plddt":91.7953,"start":444,"end":644}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P10515","model_url":"https://alphafold.ebi.ac.uk/files/AF-P10515-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P10515-F1-predicted_aligned_error_v6.png","plddt_mean":72.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DLAT","jax_strain_url":"https://www.jax.org/strain/search?query=DLAT"},"sequence":{"accession":"P10515","fasta_url":"https://rest.uniprot.org/uniprotkb/P10515.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P10515/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P10515"}},"corpus_meta":[{"pmid":"33657393","id":"PMC_33657393","title":"The phytochemical hyperforin triggers thermogenesis in adipose tissue via a Dlat-AMPK signaling axis to curb obesity.","date":"2021","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/33657393","citation_count":166,"is_preprint":false},{"pmid":"18784082","id":"PMC_18784082","title":"Crystal structure of DltA. 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Acta Academiae Medicinae Sinicae","url":"https://pubmed.ncbi.nlm.nih.gov/15562760","citation_count":0,"is_preprint":false},{"pmid":"42228272","id":"PMC_42228272","title":"MELK inhibits cuproptosis in diffuse large B-cell lymphoma cells via the PI3K/mTOR/S6K-DLAT signaling axis.","date":"2026","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/42228272","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.16.682926","title":"Integrated phenotypic and proteomic screening identifies top-tier Alzheimer’s disease therapeutic targets","date":"2025-10-16","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.16.682926","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.05.02.651901","title":"Global genome analysis identifies glycolipids and lipoteichoic acid alanylation as contributors to Group B streptococcal diabetic wound infection","date":"2025-05-02","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.02.651901","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.19.660511","title":"LiaS-dependent activation of the MadR regulon enables cross-talk between  <i>Enterococcus faecalis</i>  cell envelope defense systems","date":"2025-06-20","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.19.660511","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":43508,"output_tokens":6049,"usd":0.11063,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14833,"output_tokens":3856,"usd":0.085282,"stage2_stop_reason":"end_turn"},"total_usd":0.195912,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2021,\n      \"finding\": \"Dlat (dihydrolipoamide S-acetyltransferase) was identified as a direct molecular target of the phytochemical hyperforin (HPF) using LiP-SMap (limited proteolysis-mass spectrometry), microscale thermophoresis, and molecular docking. Ablation of Dlat significantly attenuated HPF-mediated adipose tissue browning both in vitro and in vivo, placing Dlat upstream of AMPK and PGC-1α in a thermogenic pathway.\",\n      \"method\": \"LiP-SMap, microscale thermophoresis, molecular docking, Dlat knockout/ablation with thermogenesis phenotype readout\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal biochemical methods (LiP-SMap, MST, docking) plus genetic loss-of-function in vitro and in vivo confirming functional consequence\",\n      \"pmids\": [\"33657393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Dlat interacts with transient receptor potential vanilloid 3 (Trpv3) to activate the calcium channel, increasing intracellular Ca2+ and activating CaMKKβ, which then stimulates AMPK to elevate Ucp1 expression and initiate adipose thermogenesis. HPF promotes thermogenesis by enhancing the Dlat-Trpv3 interaction independently of β3-adrenergic receptor signaling; thermogenic effects were reduced in Dlat+/- mice.\",\n      \"method\": \"Co-immunoprecipitation/interaction assays, Seahorse assays, JC-1 staining, qPCR, immunoblotting, Dlat heterozygous knockout mice on HFD\",\n      \"journal\": \"Journal of advanced research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function in vivo plus interaction assays and multiple functional readouts, single lab\",\n      \"pmids\": [\"39631519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PDC-E2 (DLAT) is constitutively present in the nucleus of BaF3 cells and functions as a co-activator of STAT5-dependent gene transcription. Nuclear PDC-E2 is lipoylated and associates with PDC-E1; IL-3-induced phosphorylated STAT5 co-immunoprecipitates with nuclear PDC-E2. PDC-E2 overexpression augments STAT5-driven reporter activity and elevates endogenous SOCS3 mRNA levels.\",\n      \"method\": \"Subcellular fractionation, co-immunoprecipitation, confocal immunofluorescence, reporter assay, qRT-PCR\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (fractionation, Co-IP, confocal, reporter assay), single lab\",\n      \"pmids\": [\"21397011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DLAT directly acetylates AU RNA-binding methylglutaconyl-CoA hydratase (AUH) at lysine 109 (K109), inhibiting its activity and causing leucine accumulation that sustains mTOR complex activation in hepatocellular carcinoma. This reveals an unexpected acetyltransferase function of DLAT beyond its canonical role in the pyruvate dehydrogenase complex.\",\n      \"method\": \"Direct acetylation assay (in vitro), site-directed mutation of AUH K109, mass spectrometry identification of acetylation site, mTOR activity readout, xenograft models with AUHK109R-mRNA LNP rescue\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic assay with mutagenesis (K109R) plus in vivo rescue experiment, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"40112809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Mitochondrial lysine methyltransferase KMT9 monomethylates DLAT at lysine 596 (K596me1) to regulate pyruvate dehydrogenase complex (PDC) activity. KMT9 depletion compromises PDC activity, de novo lipogenesis, and prostate cancer cell proliferation in vitro and in a mouse model. KMT9 localizes to mitochondria specifically in prostate cancer cells.\",\n      \"method\": \"Mass spectrometry identification of K596me1, KMT9 depletion (in vitro and in vivo mouse model), PDC activity assay, de novo lipogenesis assay, mitochondrial fractionation/localization\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — PTM identified by MS with functional validation via KO in vitro and in vivo, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"39885202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"DLAT directly binds to the mitochondrial glutathione transporter SLC25A39 and enhances its protein stability independent of intracellular GSH levels, maintaining mitochondrial GSH import and redox homeostasis. Knockdown of DLAT or SLC25A39 disrupts mtGSH transport, elevates lipid peroxidation, and sensitizes colorectal cancer cells to ferroptosis.\",\n      \"method\": \"Co-immunoprecipitation (direct binding), siRNA knockdown with ferroptosis phenotype readout (lipid peroxidation, mtGSH measurement), protein stability assay\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding demonstrated by Co-IP plus loss-of-function with specific molecular phenotype, single lab\",\n      \"pmids\": [\"42009144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"p32 (C1QBP) directly interacts with DLAT in the mitochondria, and increasing p32 expression increases oxidative phosphorylation by interacting with DLAT to regulate pyruvate dehydrogenase complex (PDHc) activation. p32 has direct binding affinity for copper and facilitates copper-induced oligomerization of lipoylated DLAT (lipo-DLAT) specifically in clear cell renal cell carcinoma (ccRCC) cells.\",\n      \"method\": \"Co-immunoprecipitation (p32-DLAT), copper binding assay, DLAT oligomerization assay, Seahorse assay (OXPHOS), animal models\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus multiple functional assays, single lab\",\n      \"pmids\": [\"38169635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MELK activates PI3K/mTOR signaling to upregulate DLAT expression and stabilize mitochondrial function in hepatocellular carcinoma. Elevated DLAT (particularly the monomeric form) promotes elesclomol drug resistance and reduces cuproptosis susceptibility. Elesclomol treatment reduced TOM20 expression and increased DLAT oligomers, and MELK-mediated effects were abolished by elesclomol treatment.\",\n      \"method\": \"siRNA knockdown, DLAT overexpression, Western blotting (DLAT monomer vs. oligomer), PI3K/mTOR pathway inhibition, xenograft models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss/gain-of-function with pathway inhibition, multiple cellular and in vivo readouts, single lab\",\n      \"pmids\": [\"37949877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DLAT functions as a cuproptosis promoter in hepatocellular carcinoma; siRNA-mediated downregulation of DLAT effectively inhibited copper ionophore (elesclomol)-induced cuproptosis in a copper-dependent manner. Selective Cu2+ chelation with ammonium tetrathiomolybdate also inhibited cuproptosis.\",\n      \"method\": \"siRNA loss-of-function, CCK8 cell viability assay, Western blotting (DLAT expression), elesclomol-copper cuproptosis induction\",\n      \"journal\": \"Current medical science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — loss-of-function with specific cell death phenotype, single lab, single main method\",\n      \"pmids\": [\"37286711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cuproptosis-upregulated DLAT inhibits autophagy, promotes G2/M phase cell cycle retention, and enhances docetaxel chemosensitivity in prostate cancer via the mTOR signaling pathway. These effects were demonstrated both in vitro and in xenograft models.\",\n      \"method\": \"Elesclomol-CuCl2 treatment, Western blotting, cell cycle flow cytometry, transmission electron microscopy, mTOR signaling analysis, xenograft model\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (flow cytometry, TEM, signaling pathway analysis, in vivo), single lab\",\n      \"pmids\": [\"37584654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PM2.5 upregulates DLAT expression through two mechanisms: (1) activating eIF4E to increase DLAT translation (shown by polysome fractionation), and (2) stimulating transcription factor Sp1 to augment DLAT promoter transcriptional activity (shown by ChIP and dual-luciferase reporter assay). Elevated DLAT promotes glycolysis but suppresses acetyl-CoA production, enhancing NSCLC malignancy.\",\n      \"method\": \"Polysome fractionation (Ribo-seq), ChIP, dual-luciferase reporter assay, Seahorse XF glycolysis stress assay, gain/loss-of-function experiments\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two distinct mechanistic pathways each supported by orthogonal methods, single lab\",\n      \"pmids\": [\"35869499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DLAT enhances glucose transporter 1 (GLUT1) expression via H3K18 acetylation, promoting aerobic glycolysis and epithelial-to-mesenchymal transition (EMT) to augment HCC metastasis. Functional cytology experiments confirmed that DLAT drives tumor metastasis by driving metabolic reprogramming.\",\n      \"method\": \"RNA sequencing, tissue microarrays, in vitro and in vivo functional assays, H3K18 acetylation analysis, Western blot\",\n      \"journal\": \"Molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — H3K18 acetylation mechanistic link supported by in vitro and in vivo experiments, single lab\",\n      \"pmids\": [\"39979835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PDC-E2 (DLAT) interacts with phosphorylated STAT3 (pY-STAT3) under cholestatic conditions in human cholangiocytes (NHC). GCDC treatment induced PDC-E2 expression and stimulated pY-STAT3 phosphorylation; siRNA silencing of PDC-E2 reduced pY-STAT3 expression specifically in NHC. Immunoprecipitation and proximity ligation assay confirmed GCDC-enhanced pY-STAT3 binding to PDC-E2 in nuclear and cytoplasmic fractions. PDC-E2/pS-STAT3 complexes were also detected in mitochondria.\",\n      \"method\": \"Co-immunoprecipitation, proximity ligation assay, siRNA knockdown, subcellular fractionation, MitoTracker co-localization\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction confirmed by two orthogonal methods (Co-IP and PLA), siRNA functional validation, single lab\",\n      \"pmids\": [\"34737337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DLAT directly interacts with YAP1, leading to dephosphorylation and activation of YAP1 and increased nuclear translocation, thereby transcriptionally activating downstream oncogenes and promoting the malignant phenotype of triple-negative breast cancer. Rescue experiments confirmed that DLAT promotes malignant behavior through a YAP1-dependent pathway.\",\n      \"method\": \"Co-immunoprecipitation, cytoplasmic-nuclear separation experiments, Western blot, rescue experiments with YAP1 manipulation\",\n      \"journal\": \"Cancer biology & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP plus nuclear translocation assay and rescue experiments, single lab\",\n      \"pmids\": [\"39460738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DLAT directly binds to CASP3 and CASP9 proteins in granulosa cells to inhibit apoptosis, and DLAT overexpression increased PCNA and MCL1 levels to promote granulosa cell proliferation. Pyruvate upregulates DLAT expression, and high DLAT levels in large follicles promote follicular growth.\",\n      \"method\": \"Protein binding assay (DLAT-CASP3/CASP9), qRT-PCR, Western blot, cell proliferation assay, in vivo follicular growth experiments\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, binding shown but method not fully specified in abstract, limited mechanistic depth\",\n      \"pmids\": [\"40136693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Dlat acts as a key transacetylase for mitochondrial protein hyperacetylation in HFpEF hearts. Dlat directly acetylates the alpha subunit of mitochondrial trifunctional protein (HADHA) at K728, inactivating HADHA enzymatic activity and inhibiting fatty acid oxidation. Dlat overexpression enhanced FAO-related protein acetylation and exacerbated cardiac lipid metabolism disturbances; Dlat knockdown mitigated FAO inhibition and HFpEF phenotypes.\",\n      \"method\": \"In vitro acetylation assay (Dlat→HADHA K728), site-specific acetylation identification by MS, Dlat KO/OE with FAO and cardiac function readouts\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic acetylation with identified substrate site, genetic loss/gain-of-function in vivo with specific metabolic and cardiac phenotype readouts\",\n      \"pmids\": [\"41826295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DLAT promotes lipid metabolism reprogramming in ovarian cancer via the JAK2/STAT5/SREBP1 signaling axis. DLAT silencing reduced lipid content and impaired OC cell proliferation, migration, and invasion. DLAT upregulated SREBP1 expression through JAK2/STAT5 signaling, enhancing fatty acid synthesis; SREBP1 was essential for DLAT-dependent OC cell growth and metastasis in vitro and in vivo.\",\n      \"method\": \"siRNA knockdown, Western blot (JAK2/STAT5/SREBP1 pathway), lipid detection assays, SREBP1 overexpression rescue, xenograft mouse model\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway placement by rescue experiment plus in vivo model, multiple methods, single lab\",\n      \"pmids\": [\"39871246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Microglial exosomes facilitate transfer of PKM2 to neurons, leading to upregulation of DLAT expression and increased copper-induced neuronal death in Alzheimer's disease context. Inhibition of PKM2 transfer via exosomes resulted in significant reduction in DLAT expression, mitigating neuronal death. DLAT was validated as increased in 5xFAD transgenic mice hippocampus.\",\n      \"method\": \"In vitro exosome transfer assay, PKM2 inhibition, siRNA/knockdown of PKM2 transfer, 5xFAD transgenic mouse model, Western blot\",\n      \"journal\": \"CNS neuroscience & therapeutics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mechanistic pathway inferred from exosome transfer experiments with limited direct evidence for DLAT-specific mechanism, single lab\",\n      \"pmids\": [\"39428563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Lipoylation of the lysine residue in the inner lipoyl domain of human PDC-E2 is crucial for effective autoantibody recognition in primary biliary cirrhosis. Purified lipoylated and unlipoylated forms of the inner lipoyl domain were compared in immunoblotting, ELISA inhibition experiments, and antibody affinity measurements; PBC autoantibodies have higher relative affinity for the lipoylated form, recognizing a unique peptide-cofactor conformation.\",\n      \"method\": \"Recombinant protein expression in E. coli, affinity purification of lipoylated/unlipoylated forms, ELISA inhibition, immunoblotting, affinity measurements\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted recombinant protein forms with multiple biochemical assays, single lab\",\n      \"pmids\": [\"7694896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"Site-directed mutagenesis of the lysine residue in the lipoyl domain of human PDC-E2 (replacing lysine with glutamine, histidine, or tyrosine) demonstrated that the recognition of the immunodominant autoepitope by PBC patient sera is dependent on the lipoyl domain structure rather than simply the charge or chemistry of the lysine sidechain alone; the recognition reflects the surface-exposed, hydrophilic, mobile nature of the lipoyl domain region.\",\n      \"method\": \"Oligonucleotide-directed site-directed mutagenesis, ELISA, immunoblotting, specific absorption assays with patient sera\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro mutagenesis with functional autoantibody recognition assays, single lab\",\n      \"pmids\": [\"1701753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"siRNA-mediated knockdown of DLAT in gastric cancer cell lines supported a role for DLAT in cell proliferation and carbohydrate metabolism, consistent with its function as a subunit of the pyruvate dehydrogenase complex involved in metabolic reprogramming in cancer.\",\n      \"method\": \"siRNA knockdown, cell proliferation assay, metabolic assays\",\n      \"journal\": \"American journal of translational research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single knockdown experiment with phenotypic readout, no pathway placement, single lab\",\n      \"pmids\": [\"26279757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"PDC-E2 (DLAT) gene was mapped to human chromosome 11 band q23.1 using fluorescence in situ hybridization, and a TaqI restriction fragment length polymorphism was identified. The chromosomal location was experimentally determined.\",\n      \"method\": \"Fluorescence in situ hybridization (FISH), RFLP analysis with restriction enzymes\",\n      \"journal\": \"Autoimmunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct FISH localization experiment, single lab but established chromosomal position\",\n      \"pmids\": [\"8102256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"NAT10 enhances DLAT mRNA stability by mediating its N4-acetylcytidine (ac4C) modification, promoting DLAT expression and cuproptosis in colorectal cancer. Lactylation of NAT10 at K426 enhances NAT10 catalytic activity, while SIRT1-mediated delactylation of NAT10-K426 inhibits cuproptosis. Elesclomol-induced reduction of soluble DLAT feeds back to enhance NAT10-K426 lactylation, creating a positive feedback loop.\",\n      \"method\": \"ac4C RNA modification assay, NAT10 knockdown/overexpression, SIRT1 inhibition (selisistat), DLAT mRNA stability assay, lactylation site identification (K426)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA modification mechanism with post-translational modification of regulator identified, multiple functional experiments, single lab\",\n      \"pmids\": [\"42085165\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DLAT (PDC-E2/dihydrolipoamide S-acetyltransferase) is the E2 subunit of the mitochondrial pyruvate dehydrogenase complex whose lipoylated form is the immunodominant autoantigen in primary biliary cholangitis; beyond its canonical metabolic role, DLAT functions as a non-canonical acetyltransferase targeting substrates including AUH (K109) and HADHA (K728) to suppress leucine catabolism and fatty acid oxidation respectively, undergoes KMT9-mediated monomethylation at K596 to regulate PDC activity, localizes to the nucleus where it co-activates STAT5-dependent transcription, interacts with Trpv3 to activate calcium-AMPK-UCP1 thermogenic signaling, and serves as the key copper-binding lipoylated protein whose oligomerization drives cuproptosis downstream of FDX1-mediated lipoic acid reduction.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DLAT (PDC-E2/dihydrolipoamide S-acetyltransferase) is the lipoylated E2 core subunit of the mitochondrial pyruvate dehydrogenase complex, and its activity is tuned by post-translational modification: KMT9 monomethylates DLAT at K596 to sustain PDC activity, de novo lipogenesis, and prostate cancer proliferation [#4]. Beyond catalysis, DLAT has emerged as a non-canonical acetyltransferase that directly acetylates substrate lysines to reprogram metabolism — it acetylates AUH at K109 to inhibit leucine catabolism and sustain mTOR activation in hepatocellular carcinoma [#3], and acetylates the trifunctional protein subunit HADHA at K728 to inactivate fatty acid oxidation in HFpEF hearts [#15]; it also drives GLUT1 expression through H3K18 acetylation to promote glycolysis and EMT in HCC [#11]. DLAT is the key copper-binding lipoylated protein of cuproptosis: copper-driven oligomerization of lipo-DLAT executes copper ionophore–induced cell death, with the monomeric versus oligomeric balance determining cuproptosis susceptibility and drug resistance, and p32/C1QBP binding facilitating copper-induced oligomerization [#6, #7, #8]. Its abundance is controlled transcriptionally (Sp1), translationally (eIF4E), and through NAT10-mediated ac4C mRNA stabilization, with elesclomol-driven depletion of soluble DLAT feeding a NAT10 lactylation feedback loop [#10, #22]. DLAT additionally localizes to the nucleus and to interaction partners that drive growth and metabolic signaling, including STAT5 co-activation [#2], YAP1 dephosphorylation/activation [#13], and a JAK2/STAT5/SREBP1 lipogenic axis [#16], and engages thermogenic signaling by interacting with Trpv3 to activate a Ca2+–CaMKKβ–AMPK–UCP1 cascade in adipose browning [#0, #1]. The lipoylated inner lipoyl domain of DLAT is the immunodominant autoantigen recognized by primary biliary cholangitis autoantibodies, where lipoylation and the surface-exposed lipoyl domain conformation determine epitope recognition [#18, #19].\",\n  \"teleology\": [\n    {\n      \"year\": 1990,\n      \"claim\": \"Established that PBC autoantibody recognition of DLAT depends on the structure of its lipoyl domain rather than on the lysine sidechain chemistry alone, defining the molecular basis of the immunodominant autoepitope.\",\n      \"evidence\": \"Site-directed mutagenesis of the lipoyl-domain lysine with ELISA/immunoblot recognition by patient sera\",\n      \"pmids\": [\"1701753\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish how lipoylation status alters the surface conformation recognized\", \"Single-lab in vitro system\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Showed that lipoylation of the inner lipoyl-domain lysine is required for high-affinity autoantibody recognition, linking the metabolic cofactor to autoimmune antigenicity in PBC.\",\n      \"evidence\": \"Comparison of recombinant lipoylated vs unlipoylated lipoyl domains by ELISA inhibition, immunoblot, and affinity measurement\",\n      \"pmids\": [\"7694896\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not address why tolerance to this self-antigen is lost in disease\", \"No structural model of the cofactor-peptide conformation\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Revealed a non-mitochondrial role: nuclear DLAT acts as a STAT5 transcriptional co-activator, indicating functions beyond the PDC core.\",\n      \"evidence\": \"Subcellular fractionation, Co-IP with phospho-STAT5, confocal, and reporter/qRT-PCR in BaF3 cells\",\n      \"pmids\": [\"21397011\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of DLAT nuclear import not defined\", \"Whether lipoyltransferase activity is required for co-activation unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified DLAT as the direct target of hyperforin and placed it upstream of AMPK/PGC-1α in adipose thermogenesis, the first functional link of DLAT to a thermogenic pathway.\",\n      \"evidence\": \"LiP-SMap, microscale thermophoresis, docking, plus Dlat ablation with thermogenesis readout in vitro and in vivo\",\n      \"pmids\": [\"33657393\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular effector downstream of DLAT not yet defined at this stage\", \"Direct binding site of hyperforin not resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined how DLAT abundance is controlled, showing PM2.5 raises DLAT via Sp1 transcription and eIF4E translation, with elevated DLAT shifting NSCLC toward glycolysis.\",\n      \"evidence\": \"Polysome fractionation, ChIP, dual-luciferase reporter, Seahorse glycolysis assay with gain/loss-of-function\",\n      \"pmids\": [\"35869499\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How elevated DLAT suppresses acetyl-CoA production mechanistically unclear\", \"Single-lab cell-based system\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established DLAT as the executor of cuproptosis, where copper-ionophore-induced death requires DLAT and depends on its monomer/oligomer state and upstream PI3K/mTOR-driven expression.\",\n      \"evidence\": \"siRNA loss-of-function, copper chelation, monomer vs oligomer Western blots, pathway inhibition, and xenografts across HCC and prostate cancer\",\n      \"pmids\": [\"37286711\", \"37949877\", \"37584654\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of copper-induced lipo-DLAT oligomerization not resolved\", \"Downstream death-execution steps after oligomerization undefined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Expanded DLAT interactomes linking it to thermogenesis, OXPHOS, and oncogenic signaling, including Trpv3-Ca2+-AMPK-UCP1, p32-facilitated copper oligomerization, and YAP1 activation.\",\n      \"evidence\": \"Co-IP/interaction assays, copper-binding and oligomerization assays, Seahorse, nuclear translocation, and rescue experiments across adipose, ccRCC, and TNBC models\",\n      \"pmids\": [\"39631519\", \"38169635\", \"39460738\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether these interactions are mitochondrial vs cytosolic/nuclear not always resolved\", \"Direct binding interfaces not mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined the non-canonical acetyltransferase function of DLAT — direct acetylation of AUH at K109 — and a KMT9-mediated K596 monomethylation that regulates PDC activity, plus H3K18ac-driven GLUT1 induction and JAK2/STAT5/SREBP1 lipogenic reprogramming.\",\n      \"evidence\": \"In vitro acetylation assays with site mutagenesis (AUH K109R), MS PTM mapping (K596me1), KMT9 depletion, chromatin acetylation analysis, and in vivo rescue/xenograft models\",\n      \"pmids\": [\"40112809\", \"39885202\", \"39979835\", \"39871246\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic mechanism of DLAT acting as a protein acetyltransferase not structurally defined\", \"Full substrate repertoire and subcellular site of acetylation incompletely mapped\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showed DLAT-driven hyperacetylation inactivates fatty acid oxidation via HADHA-K728 acetylation, stabilizes mitochondrial GSH import through SLC25A39 binding, and is itself stabilized by NAT10-mediated ac4C in a cuproptosis feedback loop.\",\n      \"evidence\": \"In vitro acetylation with MS site identification, Co-IP/protein stability assays, ac4C modification and mRNA stability assays, with genetic perturbation and in vivo cardiac/CRC models\",\n      \"pmids\": [\"41826295\", \"42009144\", \"42085165\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How DLAT switches between catalytic, acetyltransferase, and copper-binding roles is unresolved\", \"Mechanism balancing pro-cuproptotic vs ferroptosis-protective functions undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The unifying biochemical basis by which a single mitochondrial PDC subunit performs metabolic catalysis, non-canonical protein/histone acetylation, copper-driven oligomerization, and nuclear transcriptional co-activation remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structure explaining moonlighting acetyltransferase activity\", \"Determinants of DLAT subcellular partitioning between mitochondria and nucleus unknown\", \"How PTMs (K596me1, lipoylation) gate these distinct activities not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [3, 15, 11]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3, 15]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2, 13, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [4, 6, 12, 15]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 12, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [4, 10, 15, 16]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [6, 7, 8, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2, 13, 16]}\n    ],\n    \"complexes\": [\"pyruvate dehydrogenase complex\"],\n    \"partners\": [\"TRPV3\", \"STAT5\", \"STAT3\", \"YAP1\", \"C1QBP\", \"SLC25A39\", \"CASP3\", \"CASP9\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}