{"gene":"SIRT4","run_date":"2026-06-10T07:46:32","timeline":{"discoveries":[{"year":2006,"finding":"SIRT4 is a mitochondrial enzyme that uses NAD+ to ADP-ribosylate and downregulate glutamate dehydrogenase (GDH) activity in pancreatic beta cells, thereby repressing amino acid-stimulated insulin secretion. Loss of SIRT4 activates GDH; GDH from SIRT4-deficient or calorie-restricted mice is insensitive to phosphodiesterase (which cleaves ADP-ribose), confirming absence of ADP-ribosylation.","method":"Loss-of-function in insulinoma cells and SIRT4 KO mice; phosphodiesterase sensitivity assay; GDH activity assay; insulin secretion measurement","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (enzymatic assay, KO mouse, phosphodiesterase cleavage assay), replicated in cell lines and in vivo","pmids":["16959573"],"is_preprint":false},{"year":2007,"finding":"Human SIRT4 localizes to the mitochondrial matrix and is cleaved at amino acid 28 after import. SIRT4 exhibits no histone deacetylase activity but functions as an ADP-ribosyltransferase on histones and BSA. Mass spectrometry of co-immunoprecipitates identified insulin-degrading enzyme and ADP/ATP carrier proteins ANT2 and ANT3 as SIRT4-interacting proteins. Depletion of SIRT4 in INS-1E cells increases glucose-stimulated insulin secretion.","method":"Mitochondrial import/processing assay; in vitro ADP-ribosyltransferase assay; co-immunoprecipitation + mass spectrometry; SIRT4 knockdown in INS-1E cells; insulin secretion assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — reconstitution of enzymatic activity in vitro, reciprocal co-IP/MS for interactors, functional KD phenotype, multiple orthogonal methods in one study","pmids":["17715127"],"is_preprint":false},{"year":2013,"finding":"mTORC1 promotes glutamine anaplerosis by activating GDH through transcriptional repression of SIRT4. Mechanistically, mTORC1 represses SIRT4 by promoting proteasome-mediated destabilization of the transcription factor CREB2, placing SIRT4 downstream of mTORC1 in a glutaminolysis regulatory pathway.","method":"mTORC1 activation/inhibition (rapamycin); CREB2 overexpression/knockdown; proteasome inhibitor treatment; SIRT4 mRNA/protein measurement; GDH activity assay; cell proliferation and transformation assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis established by genetic and pharmacological manipulation, multiple orthogonal methods, pathway placement confirmed","pmids":["23663782"],"is_preprint":false},{"year":2013,"finding":"DNA damage induces SIRT4 expression, which represses glutamine metabolism (conversion of glutamine to TCA cycle intermediates), and this metabolic block is required for proper DNA damage response including cell cycle arrest. SIRT4 KO mice spontaneously develop lung tumors, establishing SIRT4 as a tumor suppressor that links the DNA damage response to glutamine metabolism.","method":"Genotoxic agent treatment; SIRT4 KO mouse model; glutamine metabolism flux assays; cell cycle analysis; genomic instability assays; tumor surveillance in KO mice","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse with spontaneous tumor phenotype, multiple genotoxic agents tested, metabolic flux assays, replicated across multiple stress conditions","pmids":["23562301"],"is_preprint":false},{"year":2013,"finding":"SIRT4 deacetylates and inhibits malonyl CoA decarboxylase (MCD), an enzyme producing acetyl-CoA from malonyl-CoA. SIRT4 KO mice display elevated MCD activity and decreased malonyl-CoA in skeletal muscle and adipose tissue, leading to increased fatty acid oxidation and protection against diet-induced obesity.","method":"In vitro deacetylase assay of MCD; SIRT4 KO mouse metabolic phenotyping; malonyl-CoA measurement; fatty acid oxidation assays; exercise tolerance tests","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro enzymatic assay identifying MCD as substrate, KO mouse with defined metabolic phenotype, multiple tissues examined","pmids":["23746352"],"is_preprint":false},{"year":2013,"finding":"SIRT4 represses fatty acid oxidation in the liver; SIRT4 null mice show increased PPARα target gene expression and higher rates of fatty acid oxidation in primary hepatocytes. The enhanced fatty acid oxidation in SIRT4 KO hepatocytes requires functional SIRT1, demonstrating cross-talk between mitochondrial SIRT4 and nuclear SIRT1.","method":"SIRT4 KO mouse; primary hepatocyte fatty acid oxidation assays; SIRT4 overexpression; SIRT1 inhibition in SIRT4 KO hepatocytes; PPARα target gene expression","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse + primary cells + genetic epistasis (SIRT1 required for SIRT4 KO phenotype), multiple orthogonal methods","pmids":["24043310"],"is_preprint":false},{"year":2013,"finding":"SIRT4 overexpression represses Myc-induced B cell lymphomagenesis via inhibition of mitochondrial glutamine metabolism; SIRT4 loss in Eμ-Myc transgenic mice accelerates lymphomagenesis. SIRT4 overexpression dampens glutamine utilization even in Myc-driven Burkitt lymphoma cells and sensitizes them to glucose depletion.","method":"SIRT4 overexpression in human Burkitt lymphoma cells; Eμ-Myc/SIRT4-null mouse model; glutamine uptake measurement; GDH activity assay; survival analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic mouse model with tumor phenotype, in vitro mechanistic studies, GDH activity confirmation","pmids":["24368766"],"is_preprint":false},{"year":2013,"finding":"SIRT4 regulates mitochondrial ATP homeostasis via the adenine nucleotide translocator ANT2; loss of SIRT4 decreases cellular ATP levels in vitro and in vivo, whereas SIRT4 overexpression increases ATP. SIRT4 loss activates a retrograde mitochondria-to-nucleus signaling response including AMPK, PGC1α, acetyl-CoA carboxylase, and mitochondrial respiratory machinery.","method":"SIRT4 KO and overexpression in cells and in vivo; ATP measurement; AMPK/PGC1α pathway readouts; retrograde signaling assays","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO and OE with defined ATP phenotype, AMPK pathway placement; ANT2 interaction mechanism inferred from prior co-IP data, not re-demonstrated here","pmids":["24296486"],"is_preprint":false},{"year":2013,"finding":"C. elegans SIRT4 orthologs SIR-2.2 and SIR-2.3 localize to mitochondria and function during oxidative stress. Both worm and mammalian SIRT4 interact with mitochondrial biotin-dependent carboxylases (pyruvate carboxylase PC, propionyl-CoA carboxylase PCC, methylcrotonyl-CoA carboxylase MCCC). The carboxylases are acetylated on multiple lysines; however, no changes in mPC acetylation or activity were detected upon SIRT4 overexpression or loss.","method":"Co-immunoprecipitation of SIRT4 with biotin-dependent carboxylases; mass spectrometry identification of acetylation sites; C. elegans oxidative stress assays; SIRT4 KO/OE acetylation analysis","journal":"Mitochondrion","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — co-IP identifies carboxylase interaction, negative result for PC acetylation regulation, single study","pmids":["23438705"],"is_preprint":false},{"year":2017,"finding":"SIRT4 is a lysine deacylase that removes methylglutaryl (MG)-, hydroxymethylglutaryl (HMG)-, and 3-methylglutaconyl (MGc)-lysine modifications from substrates. These acyl marks are intermediates in leucine oxidation. SIRT4 controls leucine catabolism in mice, and dysregulated leucine metabolism in SIRT4 KO mice leads to elevated basal and stimulated insulin secretion, progressing to glucose intolerance and insulin resistance with age.","method":"Phylogenetic analysis; structural biology; in vitro enzymology with defined acyl-substrates; SIRT4 KO mouse metabolic phenotyping; insulin secretion and glucose tolerance assays","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted enzymatic activity in vitro with mutagenesis, structural biology, and KO mouse phenotype in one study","pmids":["28380376"],"is_preprint":false},{"year":2016,"finding":"SIRT4 identified as the first cellular lipoamidase, removing lipoyl modifications from lysine residues of pyruvate dehydrogenase complex (PDH) subunits, thereby modulating PDH activity and acetyl-CoA production.","method":"In vitro lipoamidase assay; PDH activity measurement; identification via SIRT4 interaction proteomics","journal":"Methods in molecular biology (Clifton, N.J.)","confidence":"Medium","confidence_rationale":"Tier 1-2 / Weak — enzymatic activity described in methods/protocol paper citing prior findings; original experimental demonstration referenced but not fully detailed in this abstract","pmids":["27246218"],"is_preprint":false},{"year":2017,"finding":"SIRT4 physically interacts with OPA1 (the dynamin-related GTPase regulating inner mitochondrial membrane fusion) via co-immunoprecipitation. Moderate SIRT4 overexpression (enzymatically active but not H161Y mutant) increases long-form L-OPA1, promoting mitochondrial fusion and counteracting fission/mitophagy. Endogenous SIRT4 upregulation (via miR-15b inhibition or ionizing radiation) similarly increases L-OPA1 and fusion.","method":"Co-immunoprecipitation of SIRT4 and OPA1; SIRT4 overexpression including H161Y catalytic mutant; mitochondrial morphology imaging; mitophagy flux assays; miR-15b inhibitor treatment; ionizing radiation senescence model","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — co-IP of SIRT4-OPA1, enzymatic mutant controls, functional morphology readouts; single lab","pmids":["29081403"],"is_preprint":false},{"year":2016,"finding":"SIRT4 inhibits mitochondrial fission in NSCLC cells by inhibiting Drp1 phosphorylation and weakening Drp1 recruitment to the mitochondrial membrane via interaction with Fis-1. SIRT4 expression also suppresses MEK/ERK activity, implicating the ERK-Drp1 pathway in SIRT4-mediated inhibition of cancer cell invasion and migration.","method":"SIRT4 plasmid transfection and siRNA in lung cancer cell lines; confocal microscopy for mitochondrial localization; phospho-Drp1 western blot; Drp1-Fis1 interaction assay; invasion/migration assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — multiple functional readouts, phosphorylation analysis, single lab","pmids":["27941873"],"is_preprint":false},{"year":2019,"finding":"SIRT4 interacts with PTEN and promotes its degradation through the lysosomal pathway mediated by insulin-degrading enzyme (IDE). SIRT4 bridges PTEN and IDE for degradation in response to nutritional starvation. This regulation is independent of PTEN acetylation and ubiquitination. Induction of SIRT4 during nutrient starvation reduces PTEN levels to promote cell survival.","method":"Co-immunoprecipitation of SIRT4-PTEN and SIRT4-IDE; SIRT4 overexpression/knockdown; lysosome pathway inhibitors; ubiquitination/acetylation analysis; nutritional starvation stress model","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — co-IP of three-protein complex, lysosome pathway validation, single lab","pmids":["30649986"],"is_preprint":false},{"year":2020,"finding":"SIRT4 inhibits the anaplerotic conversion of glutamine to α-ketoglutarate, which potentiates TORC1 signaling (retrograde mitochondria-to-nucleus signaling). SIRT4 is induced in the fed state and activates TORC1 while inhibiting AMPK-PGC1α/SIRT1-PPARα catabolic signaling, thereby regulating lipogenesis, autophagy, and cell proliferation.","method":"SIRT4 KO and overexpression; TORC1 activity assays; glutamine metabolism flux; AMPK and PPARα pathway measurements; fed/fasted state comparison","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO and OE with multiple pathway readouts, mechanistic epistasis established, single lab","pmids":["31685549"],"is_preprint":false},{"year":2020,"finding":"PAK6 (a serine/threonine kinase) forms a complex with SIRT4 and ANT2 in the mitochondrial inner membrane. PAK6 promotes SIRT4 ubiquitin-mediated proteolysis. SIRT4 deacetylates ANT2 at K105, promoting its ubiquitination and degradation. Thus PAK6 adjusts ANT2 acetylation through the PAK6-SIRT4-ANT2 axis to regulate prostate cancer cell apoptosis.","method":"Co-immunoprecipitation of PAK6-SIRT4-ANT2; immunoelectron microscopy for PAK6 mitochondrial localization; ubiquitination assay; site-specific acetylation analysis of ANT2-K105; xenograft model; flow cytometry for apoptosis","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — reciprocal co-IP, site-specific modification identified, in vivo xenograft, single lab","pmids":["32194820"],"is_preprint":false},{"year":2021,"finding":"SIRT4 elevates BCAA catabolism through activation of methylcrotonyl-CoA carboxylase (MCCC) during early adipogenesis, promoting BCAA flux and subsequent PPARγ activation and adipocyte differentiation.","method":"Metabolite consumption profiling during adipocyte differentiation; SIRT4 KO; MCCC activity assays; leucine oxidation measurement; PPARγ pathway readouts","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO with metabolic flux assays and MCCC activity measurement, pathway placement established, single lab","pmids":["34260923"],"is_preprint":false},{"year":2022,"finding":"SIRT4 deacetylates MTHFD2 at lysine 50 (K50), destabilizing MTHFD2 via cullin 3 E3 ligase-mediated proteasomal degradation in response to folate deprivation stress. This suppresses NADPH production and leads to ROS accumulation, inhibiting breast cancer cell growth.","method":"In vitro deacetylation assay; site-directed mutagenesis of K50; cullin 3 ubiquitination assay; SIRT4 KO/OE; NADPH measurement; ROS measurement; folate deprivation stress model","journal":"Journal of molecular cell biology","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro enzymatic assay with site mutagenesis, ubiquitination confirmation, single lab","pmids":["35349697"],"is_preprint":false},{"year":2022,"finding":"SIRT4 ADP-ribosylates MAT2A at glutamic acid 111, inhibiting its activity. In HCC, the mTORC1-c-Myc axis drives TRIM32-mediated degradation of SIRT4; loss of SIRT4 activates MAT2A, increasing S-adenosylmethionine (SAM) levels and promoting gene expression changes that support tumor proliferation.","method":"ADP-ribosylation assay of MAT2A; site identification (E111); TRIM32 ubiquitination assay; SIRT4 KO/OE; SAM metabolite measurement; mTORC1/c-Myc pathway analysis; xenograft and dietary methionine restriction models","journal":"Cell & bioscience","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — enzymatic activity with substrate site identified, upstream degradation mechanism defined, single lab","pmids":["36371321"],"is_preprint":false},{"year":2022,"finding":"SIRT4 translocates from mitochondria to the cytoplasm and then to the nucleus in response to TGF-β stimulation. In the nucleus, SIRT4 deacetylates U2AF2 at K413, facilitating splicing of CCN2 pre-mRNA and promoting CCN2 protein expression, thereby driving renal fibrosis. TGF-β activates ERK, inducing phosphorylation of SIRT4 at Ser36, promoting its interaction with importin α1 and nuclear translocation.","method":"TGF-β stimulation; SIRT4 nuclear fractionation; BAX/BAK pore inhibition; ERK pathway inhibition; phosphorylation of SIRT4 S36; importin α1 co-immunoprecipitation; SIRT4 deacetylation of U2AF2 K413; alternative splicing analysis; SIRT4 TEC-specific KO mouse; UUO fibrosis model","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mechanistic pathway from stimulus to nuclear translocation to substrate deacetylation defined by multiple orthogonal methods including KO mouse, phosphorylation site mapping, and splicing analysis","pmids":["39495216"],"is_preprint":false},{"year":2022,"finding":"Upon Wnt stimulation, SIRT4 translocates from mitochondria to the cytoplasm where it deacetylates Axin1 at K147 (in the RGS domain). Deacetylation of Axin1-K147 impairs β-TrCP assembly into the destruction complex, leading to β-catenin accumulation and activation of canonical Wnt signaling.","method":"SIRT4 subcellular fractionation after Wnt stimulation; co-immunoprecipitation of SIRT4-Axin1; Axin1-K147R mutation; β-catenin accumulation assay; β-TrCP complex assembly assay; luciferase reporter for Wnt activity","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — site-specific mutagenesis of substrate, co-IP, functional pathway readout; single lab, SIRT4 deacylase activity assumed but not directly reconstituted in vitro","pmids":["35707358"],"is_preprint":false},{"year":2023,"finding":"SIRT4 acts as a decarbamylase that removes carbamyl groups from ornithine transcarbamylase (OTC) at lysine 307 in an NAD+-dependent manner, inactivating OTC. Amino acid sufficiency downregulates SIRT4 expression (via suppression of the GCN2-eIF2α-ATF4 axis), allowing OTC K307 carbamylation to activate the urea cycle and detoxify ammonia. SIRT4 KO increases urea cycle activity and reduces blood ammonia.","method":"Proteomic/interactome screening; co-immunoprecipitation of SIRT4-OTC; in vitro decarbamylase assay; OTC K307 carbamylation measurement; GCN2-eIF2α-ATF4 pathway analysis; SIRT4 KO mouse; CCl4-hepatic encephalopathy model","journal":"Nature metabolism","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — novel enzymatic activity (decarbamylase) reconstituted in vitro with substrate site identified, KO mouse with in vivo phenotype, upstream regulatory pathway defined","pmids":["37081161"],"is_preprint":false},{"year":2023,"finding":"SIRT4 deacetylates GNPAT (glyceronephosphate O-acyltransferase), regulating its acetylation and protein stability in the context of CSE-induced ferroptosis in COPD. GNPAT knockdown mitigated CSE-induced ferroptosis. SIRT4 overexpression suppresses ferroptosis; GNPAT overexpression reverses this inhibition.","method":"Immunoprecipitation for GNPAT acetylation; SIRT4 OE/KD; GNPAT KD; ROS/lipid ROS/GPX4 measurements; COPD mouse model with cigarette smoke; A549 cell CSE treatment","journal":"Respiratory research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — co-IP for acetylation, genetic epistasis via rescue experiment, single lab","pmids":["38041059"],"is_preprint":false},{"year":2024,"finding":"SIRT4 deacetylates HSP60 to facilitate assembly of the HSP60-HSP10 complex, which maintains activity of mitochondrial ETC complexes II and III, sustaining ATP generation and reducing ROS in the context of burn sepsis. Glutamine activates SIRT4 by upregulating its synthesis and raising NAD+ levels.","method":"SIRT4 OE/KD; HSP60 acetylation measurement; HSP60-HSP10 complex assembly assay; ETC complex II/III activity; ATP and ROS measurement; NAD+ measurement; burn sepsis mouse model","journal":"Redox report","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — acetylation-dependent complex assembly demonstrated, functional ETC readout, single lab","pmids":["38329114"],"is_preprint":false},{"year":2024,"finding":"SIRT4 downregulation in chondrocytes inhibits PINK1, impairing mitophagy and causing accumulation of ROS and damaged mitochondria, leading to chondrocyte senescence. SIRT4 overexpression rescues PINK1-mediated mitophagy and protects against TBHP-induced senescence. PINK1 overexpression counteracts the effects of SIRT4 knockdown.","method":"SIRT4 KD/OE in chondrocytes; PINK1 expression analysis; mitochondrial morphology/membrane potential/ROS/ATP measurement; PINK1 OE rescue experiment; OA mouse model; lentiviral gene therapy","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (PINK1 rescues SIRT4 KD), in vivo OA model, multiple mitochondrial readouts; single lab","pmids":["38385071"],"is_preprint":false},{"year":2025,"finding":"SIRT4 directly deacetylates ENO1 (enolase 1) at K358, reducing ENO1's RNA-binding capacity while enhancing its glycolytic substrate 2-PG affinity and catalytic activity. This increases glycolytic flux and lactate production. Elevated lactate drives histone lactylation at H3K9 and H3K18, causing epigenetic reprogramming that activates stemness pathways in pancreatic tumor-initiating cells. SIRT4 expression is upregulated by α2δ1-mediated calcium signaling.","method":"SIRT4 OE/KD in pancreatic TICs; in vitro deacetylation of ENO1-K358; ENO1 mutant analysis (RNA binding and enzymatic activity); glycolytic flux measurement; lactate measurement; histone lactylation (H3K9lac, H3K18lac) ChIP; sphere formation and TIC assays; calcium channel manipulation","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro enzymatic assay with site mutagenesis, histone modification ChIP validation, single lab; novel context-dependent oncogenic role","pmids":["40298941"],"is_preprint":false},{"year":2015,"finding":"CtBP directly represses SIRT4 gene expression at the transcriptional level in cancer cells, promoting glutaminolysis by allowing GDH activity to proceed unchecked; this coordinates glucose and glutamine metabolism. High glucose maintains CtBP dimerization and promoter binding to repress SIRT4, whereas low glucose abolishes CtBP binding to the SIRT4 promoter.","method":"CtBP knockdown/overexpression; SIRT4 promoter ChIP; CtBP dimerization inhibitor MTOB; GDH activity assay; glutamine consumption measurement; pH homeostasis assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for promoter binding, pharmacological and genetic manipulation, GDH activity confirmation; single lab","pmids":["25633289"],"is_preprint":false},{"year":2017,"finding":"FOXQ1, a forkhead transcription factor, maintains SIRT4 expression in young cells. In senescence, FOXQ1 and SIRT4 expression decrease, leading to de-repression of GDH from SIRT4-mediated ADP-ribosylation. Elevated GDH activity increases α-ketoglutarate production, which drives histone demethylation (loss of H3K9me3) at IL-6 and IL-8 promoters, activating SASP.","method":"Transcription factor analysis; FOXQ1 and SIRT4 manipulations; GDH activity assay; α-KG measurement; H3K9me3 ChIP at IL-6/IL-8 promoters; GDH inhibitor treatment; senescence models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, enzymatic activity, genetic manipulations with pathway epistasis; single lab","pmids":["37516739"],"is_preprint":false},{"year":2021,"finding":"FOXM1 binds to the SIRT4 promoter to induce its transcriptional activation; SIRT4 then suppresses NF-κB signaling and the NLRP3 inflammasome, protecting against podocyte pyroptosis in diabetic nephropathy. SIRT4 downregulation blocked FOXM1's protective effects.","method":"FOXM1 promoter binding assay (chromatin); SIRT4 OE/KD; NF-κB phosphorylation; NLRP3/caspase-1 expression; pyroptosis assay; diabetic mouse model","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — promoter binding confirmed, genetic epistasis (SIRT4 KD reverses FOXM1 effect), in vivo model; single lab","pmids":["34626587"],"is_preprint":false},{"year":2017,"finding":"Lsd1 (lysine-specific demethylase 1) directly represses Sirt4 gene expression in trophoblast stem cells. Inactivation of Lsd1 causes Sirt4 upregulation, leading to decreased glutamine anaplerosis and mitochondrial function, triggering senescence. Sirt4 knockdown in Lsd1-deficient TSCs restores glutamine anaplerosis, redox balance, and mitochondrial function.","method":"Lsd1 deletion/inhibition; genome-wide transcriptional profiling; global metabolomics; Sirt4 knockdown rescue experiment; glutamine anaplerosis measurement; mitochondrial function assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis by double manipulation (Lsd1 KO + Sirt4 KD rescue), metabolomics, single lab","pmids":["28230862"],"is_preprint":false},{"year":2012,"finding":"SIRT4 localizes to mitochondria within the brain, is highly expressed in astrocytes and radial glia (but not neurons). SIRT4 and GDH1 overexpression play antagonistic roles in regulating gliogenesis in radial glial cells: SIRT4 (via ADP-ribosylation and inhibition of GDH1) opposes GDH1-driven acceleration of glial development.","method":"Subcellular fractionation/immunofluorescence in brain tissue; SIRT4 and GDH1 overexpression in CTX8 radial glial cell line; gliogenesis assays","journal":"Glia","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — localization confirmed in brain cells, functional antagonism in gliogenesis established; single lab, mechanism inferred from GDH1 inhibition","pmids":["23281078"],"is_preprint":false},{"year":2014,"finding":"Loss of SIRT4 leads to decreased expression and function of glutamate transporter GLT-1 in the brain, and increased sensitivity to kainic acid (excitotoxin). SIRT4 is upregulated in response to kainic acid treatment, suggesting a stress-responsive role in maintaining glutamate transport capacity.","method":"SIRT4 KO mouse; kainic acid treatment; GLT-1 expression and glutamate uptake assay; seizure severity measurement","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with defined transporter expression and function readouts, single lab","pmids":["25196144"],"is_preprint":false},{"year":2019,"finding":"SIRT4 protects intestinal fibrosis by facilitating GLS1 (glutaminase 1) degradation; SIRT4 hinders SIRT5's stabilizing interaction with GLS1, promoting GLS1 degradation. This reduces glutaminolysis and decreases α-ketoglutarate, which limits KDM6-mediated H3K27me3 erasure at ECM gene promoters, thereby maintaining H3K27me3-dependent repression of ECM components.","method":"SIRT4 KO/OE; GLS1 stability assay; SIRT5-GLS1 interaction co-IP; SIRT4-SIRT5-GLS1 competition assay; α-KG measurement; H3K27me3 ChIP; ECM gene expression; intestinal fibrosis mouse model","journal":"Matrix biology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — co-IP for protein interactions, histone modification ChIP, functional fibrosis model; single lab","pmids":["37541633"],"is_preprint":false}],"current_model":"SIRT4 is a mitochondrially localized NAD+-dependent enzyme with multiple enzymatic activities — ADP-ribosyltransferase (targeting GDH to repress glutamine catabolism and insulin secretion), lysine deacylase removing MG/HMG/MGc acyl groups (regulating leucine catabolism), deacetylase (targeting MCD to control lipid metabolism, MTHFD2 and HSP60 to regulate folate metabolism and ETC assembly), lipoamidase (delipoylating PDH), and decarbamylase (inactivating OTC to regulate the urea cycle); under specific stimuli such as Wnt or TGF-β signaling, SIRT4 translocates from mitochondria to the cytoplasm or nucleus to deacetylate Axin1 (modulating Wnt/β-catenin signaling) or U2AF2 (modulating alternative splicing of CCN2 to drive fibrosis), respectively; SIRT4 is transcriptionally repressed by mTORC1 (via CREB2 destabilization), CtBP, and Lsd1, and is induced by DNA damage and genotoxic stress, placing it at the intersection of nutrient sensing, metabolic regulation, DNA damage response, and tumor suppression."},"narrative":{"mechanistic_narrative":"SIRT4 is a mitochondrial-matrix NAD+-dependent enzyme that functions as a central node coupling amino acid and lipid metabolism to nutrient sensing, the DNA damage response, and tumor suppression [PMID:16959573, PMID:23562301]. Its founding activity is ADP-ribosylation of glutamate dehydrogenase (GDH), which represses glutamine/amino acid-stimulated insulin secretion in pancreatic beta cells and constrains glutamine anaplerosis into the TCA cycle [PMID:16959573, PMID:17715127]. Beyond ADP-ribosyltransferase activity, SIRT4 carries an unusually broad catalytic repertoire: it is a lysine deacylase that removes methylglutaryl, hydroxymethylglutaryl and 3-methylglutaconyl marks to control leucine catabolism [PMID:28380376], a lipoamidase that delipoylates the pyruvate dehydrogenase complex [PMID:27246218], and a decarbamylase that inactivates ornithine transcarbamylase at K307 to gate the urea cycle [PMID:37081161]. As a deacetylase it targets malonyl-CoA decarboxylase to suppress fatty acid oxidation [PMID:23746352], MTHFD2 (K50) to couple folate metabolism to redox balance [PMID:35349697], and HSP60 to sustain electron transport chain complex assembly [PMID:38329114]. Through repression of glutamine metabolism SIRT4 enforces cell-cycle arrest after genotoxic stress and restrains Myc-driven lymphomagenesis, and SIRT4-null mice spontaneously develop tumors [PMID:23562301, PMID:24368766]. SIRT4 expression is set by converging transcriptional and degradative controls: it is repressed by mTORC1 (via CREB2 destabilization), CtBP and Lsd1, induced by FOXM1, FOXQ1 and DNA damage, and degraded via PAK6 and TRIM32 [PMID:23663782, PMID:25633289, PMID:28230862, PMID:23562301, PMID:36371321]. Under defined stimuli SIRT4 leaves the mitochondrion: TGF-β-driven ERK phosphorylation at Ser36 promotes importin-α1-dependent nuclear import where SIRT4 deacetylates the splicing factor U2AF2 (K413) to drive CCN2 splicing and fibrosis [PMID:39495216], and Wnt stimulation drives cytoplasmic deacetylation of Axin1 (K147) to activate β-catenin signaling [PMID:35707358]. SIRT4 also shapes mitochondrial dynamics and quality control, interacting with OPA1 to favor fusion and supporting PINK1-dependent mitophagy [PMID:29081403, PMID:38385071].","teleology":[{"year":2006,"claim":"Established SIRT4's founding biochemical activity and physiological output by showing it ADP-ribosylates GDH to repress amino acid-stimulated insulin secretion, defining a mitochondrial sirtuin acting on metabolism rather than chromatin.","evidence":"Loss-of-function in insulinoma cells and SIRT4 KO mice with phosphodiesterase sensitivity and GDH/insulin secretion assays","pmids":["16959573"],"confidence":"High","gaps":["Did not resolve the full substrate range beyond GDH","ADP-ribosylation site on GDH not mapped"]},{"year":2007,"claim":"Localized SIRT4 to the mitochondrial matrix with N-terminal processing, confirmed in vitro ADP-ribosyltransferase activity and absence of classical HDAC activity, and identified IDE and ANT2/ANT3 as interactors.","evidence":"Mitochondrial import/processing assay, in vitro enzymology, co-IP/MS, and SIRT4 knockdown in INS-1E cells","pmids":["17715127"],"confidence":"High","gaps":["Functional consequence of ANT/IDE interactions not established here","Histone ADP-ribosylation in vitro of uncertain physiological relevance"]},{"year":2013,"claim":"Placed SIRT4 within nutrient-sensing and tumor-suppression circuits: mTORC1 represses SIRT4 (via CREB2 destabilization) to license glutamine anaplerosis, while DNA damage induces SIRT4 to block glutamine metabolism and enforce cell-cycle arrest, with SIRT4-null mice developing tumors.","evidence":"Pharmacological/genetic mTORC1 and CREB2 manipulation; genotoxic treatment; SIRT4 KO mouse tumor surveillance; metabolic flux assays","pmids":["23663782","23562301","24368766"],"confidence":"High","gaps":["Direct enzymatic link between SIRT4 and cell-cycle machinery not defined","Tissue specificity of tumor suppression incompletely mapped"]},{"year":2013,"claim":"Extended SIRT4 beyond glutamine to lipid handling and energy homeostasis, identifying MCD as a deacetylation substrate that restrains fatty acid oxidation, demonstrating SIRT1-dependent cross-talk, and linking SIRT4 to ANT2-mediated ATP homeostasis and AMPK/PGC1α retrograde signaling.","evidence":"In vitro MCD deacetylase assay; SIRT4 KO metabolic phenotyping; primary hepatocyte FAO assays; SIRT1 epistasis; ATP and AMPK/PGC1α readouts","pmids":["23746352","24043310","24296486"],"confidence":"Medium","gaps":["ANT2 interaction inferred from prior co-IP, not re-demonstrated","Mechanism of mitochondria-to-nucleus signaling not fully defined"]},{"year":2017,"claim":"Reframed SIRT4 as a robust lysine deacylase by reconstituting removal of MG/HMG/MGc acyl marks (leucine-oxidation intermediates), connecting this activity to leucine catabolism and age-dependent glucose intolerance.","evidence":"Phylogenetics, structural biology, in vitro acyl-substrate enzymology with mutagenesis, and SIRT4 KO mouse metabolic phenotyping","pmids":["28380376"],"confidence":"High","gaps":["Full set of endogenous deacylation substrates not enumerated","Relative cellular contribution of deacylase vs ADP-ribosyltransferase activity unresolved"]},{"year":2016,"claim":"Broadened SIRT4's catalytic repertoire to a lipoamidase that delipoylates PDH subunits, linking it directly to acetyl-CoA production, and documented carboxylase interactions without measurable acetylation regulation.","evidence":"In vitro lipoamidase assay and PDH activity measurement; co-IP of biotin-dependent carboxylases with negative acetylation result","pmids":["27246218","23438705"],"confidence":"Medium","gaps":["Lipoamidase activity described in a methods paper citing prior work, not fully detailed","Functional role of carboxylase binding unclear given absence of acetylation change"]},{"year":2017,"claim":"Implicated SIRT4 in mitochondrial dynamics, showing enzymatically active SIRT4 interacts with OPA1 to favor fusion and inhibits Drp1-mediated fission via Fis1, restraining cancer cell invasion.","evidence":"Co-IP of SIRT4-OPA1 with H161Y catalytic mutant controls; phospho-Drp1 and Drp1-Fis1 assays; mitochondrial morphology and invasion readouts","pmids":["29081403","27941873"],"confidence":"Medium","gaps":["Whether OPA1/Drp1 are direct enzymatic substrates not established","Single-lab observations without independent replication"]},{"year":2019,"claim":"Revealed a non-catalytic scaffolding role in which SIRT4 bridges PTEN and IDE to drive lysosomal PTEN degradation during nutrient starvation, independent of PTEN modification.","evidence":"Co-IP of SIRT4-PTEN-IDE; lysosome inhibitors; ubiquitination/acetylation analysis; starvation stress model","pmids":["30649986"],"confidence":"Medium","gaps":["Mechanism of complex assembly not structurally defined","Single Co-IP-based three-protein complex without reconstitution"]},{"year":2020,"claim":"Resolved a context-dependent reversal of SIRT4-AMPK signaling, with SIRT4 induced in the fed state to potentiate TORC1 and suppress catabolic AMPK-PGC1α/SIRT1-PPARα programs, and defined a PAK6-SIRT4-ANT2 ubiquitination axis controlling apoptosis.","evidence":"SIRT4 KO/OE with TORC1, AMPK and PPARα readouts; reciprocal PAK6-SIRT4-ANT2 co-IP, ANT2-K105 acetylation/ubiquitination, xenograft and apoptosis assays","pmids":["31685549","32194820"],"confidence":"Medium","gaps":["Reconciliation of fed-state TORC1 activation with mTORC1 repression of SIRT4 not fully integrated","PAK6 axis demonstrated in single tumor context"]},{"year":2022,"claim":"Defined SIRT4 nucleocytoplasmic translocation as a regulated signaling event, showing TGF-β/ERK-driven Ser36 phosphorylation and importin-α1-dependent nuclear import enabling U2AF2-K413 deacetylation and pro-fibrotic CCN2 splicing, and Wnt-induced cytoplasmic Axin1-K147 deacetylation activating β-catenin.","evidence":"Subcellular fractionation; S36 phospho-mapping; importin-α1 co-IP; U2AF2/Axin1 site-specific deacetylation and mutagenesis; splicing/β-catenin readouts; TEC-specific KO and UUO models","pmids":["39495216","35707358"],"confidence":"High","gaps":["Generality of translocation across cell types and stimuli unknown","Axin1 deacylase activity not directly reconstituted in vitro"]},{"year":2022,"claim":"Established additional enzymatic substrates linking SIRT4 to one-carbon, redox and methionine metabolism, with deacetylation of MTHFD2 (K50) triggering cullin3 degradation and ROS accumulation, and ADP-ribosylation of MAT2A (E111) controlling SAM levels downstream of mTORC1-c-Myc-TRIM32-mediated SIRT4 degradation.","evidence":"In vitro deacetylation/ADP-ribosylation with site mutagenesis; cullin3/TRIM32 ubiquitination assays; NADPH/ROS/SAM measurement; xenograft and dietary models","pmids":["35349697","36371321"],"confidence":"Medium","gaps":["Tissue specificity of these substrate relationships not broadly tested","Single-lab findings"]},{"year":2023,"claim":"Identified a fourth catalytic activity, NAD+-dependent decarbamylation of OTC at K307, integrating amino acid sufficiency (via GCN2-eIF2α-ATF4 control of SIRT4) into urea-cycle regulation and ammonia detoxification.","evidence":"Interactome screening, SIRT4-OTC co-IP, in vitro decarbamylase assay, K307 carbamylation measurement, GCN2 axis analysis, KO mouse and CCl4 encephalopathy model","pmids":["37081161"],"confidence":"High","gaps":["Whether decarbamylation generalizes to other carbamylated proteins unknown","Structural basis of the activity not solved"]},{"year":2023,"claim":"Connected SIRT4 to mitochondrial quality control and ferroptosis/fibrosis programs through deacetylation of HSP60 (ETC complex assembly), GNPAT (ferroptosis), GLS1 degradation via competition with SIRT5, and PINK1-dependent mitophagy.","evidence":"SIRT4 OE/KD with acetylation, complex assembly, ETC activity, ROS, PINK1 rescue, GLS1 stability and SIRT5 competition assays in disease models","pmids":["38329114","38041059","37541633","38385071"],"confidence":"Medium","gaps":["Direct vs indirect substrate relationships not all reconstituted in vitro","Each role demonstrated in a single disease context and lab"]},{"year":2025,"claim":"Revealed a context-dependent oncogenic facet, with SIRT4 deacetylating ENO1 (K358) to favor glycolytic over RNA-binding function, raising lactate to drive histone lactylation and stemness in pancreatic tumor-initiating cells.","evidence":"In vitro ENO1-K358 deacetylation, mutant analysis, glycolytic flux/lactate measurement, H3K9/H3K18 lactylation ChIP and TIC assays","pmids":["40298941"],"confidence":"Medium","gaps":["Reconciliation with established tumor-suppressor roles not resolved","Single-lab, single tumor type"]},{"year":null,"claim":"How SIRT4's multiple enzymatic activities are selectively engaged on specific substrates across tissues and stress states, and what governs the choice between mitochondrial metabolic versus extramitochondrial signaling functions, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model for activity/substrate selection","Determinants of tumor-suppressive vs oncogenic outcomes undefined","Structural basis for the diverse acyl/decarbamylase/ADP-ribosyl activities incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[4,9,10,17,19,20,21,22,23,25]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,18]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[9,10,21]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[4,17]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,1,8,30]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[19]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[19,20]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,4,9,21]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,6,18,25]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,14,19,20]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[19]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[24]}],"complexes":[],"partners":["GDH","ANT2","OPA1","PTEN","IDE","PAK6","U2AF2","OTC"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y6E7","full_name":"NAD-dependent protein lipoamidase sirtuin-4, mitochondrial","aliases":["NAD-dependent ADP-ribosyltransferase sirtuin-4","NAD-dependent protein biotinylase sirtuin-4","NAD-dependent protein deacetylase sirtuin-4","Regulatory protein SIR2 homolog 4","SIR2-like protein 4"],"length_aa":314,"mass_kda":35.2,"function":"Acts as a NAD-dependent protein lipoamidase, biotinylase, deacetylase and ADP-ribosyl transferase (PubMed:16959573, PubMed:17715127, PubMed:24052263, PubMed:25525879). Catalyzes more efficiently removal of lipoyl- and biotinyl- than acetyl-lysine modifications (PubMed:24052263, PubMed:25525879). Inhibits the pyruvate dehydrogenase complex (PDH) activity via the enzymatic hydrolysis of the lipoamide cofactor from the E2 component, DLAT, in a phosphorylation-independent manner (PubMed:25525879). Catalyzes the transfer of ADP-ribosyl groups onto target proteins, including mitochondrial GLUD1, inhibiting GLUD1 enzyme activity (PubMed:16959573, PubMed:17715127). Acts as a negative regulator of mitochondrial glutamine metabolism by mediating mono ADP-ribosylation of GLUD1: expressed in response to DNA damage and negatively regulates anaplerosis by inhibiting GLUD1, leading to block metabolism of glutamine into tricarboxylic acid cycle and promoting cell cycle arrest (PubMed:16959573, PubMed:17715127). In response to mTORC1 signal, SIRT4 expression is repressed, promoting anaplerosis and cell proliferation (PubMed:23663782). Acts as a tumor suppressor (PubMed:23562301, PubMed:23663782). Also acts as a NAD-dependent protein deacetylase: mediates deacetylation of 'Lys-471' of MLYCD, inhibiting its activity, thereby acting as a regulator of lipid homeostasis (By similarity). Does not seem to deacetylate PC (PubMed:23438705). Controls fatty acid oxidation by inhibiting PPARA transcriptional activation (PubMed:24043310). Impairs SIRT1-PPARA interaction probably through the regulation of NAD(+) levels (PubMed:24043310). Down-regulates insulin secretion (PubMed:17715127)","subcellular_location":"Mitochondrion matrix","url":"https://www.uniprot.org/uniprotkb/Q9Y6E7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SIRT4","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SIRT4","total_profiled":1310},"omim":[{"mim_id":"606212","title":"SIRTUIN 7; SIRT7","url":"https://www.omim.org/entry/606212"},{"mim_id":"606211","title":"SIRTUIN 6; SIRT6","url":"https://www.omim.org/entry/606211"},{"mim_id":"604483","title":"SIRTUIN 5; SIRT5","url":"https://www.omim.org/entry/604483"},{"mim_id":"604482","title":"SIRTUIN 4; SIRT4","url":"https://www.omim.org/entry/604482"},{"mim_id":"604481","title":"SIRTUIN 3; SIRT3","url":"https://www.omim.org/entry/604481"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SIRT4"},"hgnc":{"alias_symbol":["SIR2L4"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y6E7","domains":[{"cath_id":"3.40.50.1220","chopping":"42-311","consensus_level":"medium","plddt":96.1522,"start":42,"end":311}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y6E7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y6E7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y6E7-F1-predicted_aligned_error_v6.png","plddt_mean":90.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SIRT4","jax_strain_url":"https://www.jax.org/strain/search?query=SIRT4"},"sequence":{"accession":"Q9Y6E7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y6E7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y6E7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y6E7"}},"corpus_meta":[{"pmid":"16959573","id":"PMC_16959573","title":"SIRT4 inhibits glutamate 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SIRT4.","date":"2018","source":"Oncogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/29540733","citation_count":59,"is_preprint":false},{"pmid":"16959562","id":"PMC_16959562","title":"Insulin secretion: SIRT4 gets in on the act.","date":"2006","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/16959562","citation_count":59,"is_preprint":false},{"pmid":"31447696","id":"PMC_31447696","title":"SIRT4 and Its Roles in Energy and Redox Metabolism in Health, Disease and During Exercise.","date":"2019","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/31447696","citation_count":58,"is_preprint":false},{"pmid":"34626587","id":"PMC_34626587","title":"FOXM1-activated SIRT4 inhibits NF-κB signaling and NLRP3 inflammasome to alleviate kidney injury and podocyte pyroptosis in diabetic nephropathy.","date":"2021","source":"Experimental cell 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Loss of SIRT4 activates GDH; GDH from SIRT4-deficient or calorie-restricted mice is insensitive to phosphodiesterase (which cleaves ADP-ribose), confirming absence of ADP-ribosylation.\",\n      \"method\": \"Loss-of-function in insulinoma cells and SIRT4 KO mice; phosphodiesterase sensitivity assay; GDH activity assay; insulin secretion measurement\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (enzymatic assay, KO mouse, phosphodiesterase cleavage assay), replicated in cell lines and in vivo\",\n      \"pmids\": [\"16959573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Human SIRT4 localizes to the mitochondrial matrix and is cleaved at amino acid 28 after import. SIRT4 exhibits no histone deacetylase activity but functions as an ADP-ribosyltransferase on histones and BSA. Mass spectrometry of co-immunoprecipitates identified insulin-degrading enzyme and ADP/ATP carrier proteins ANT2 and ANT3 as SIRT4-interacting proteins. Depletion of SIRT4 in INS-1E cells increases glucose-stimulated insulin secretion.\",\n      \"method\": \"Mitochondrial import/processing assay; in vitro ADP-ribosyltransferase assay; co-immunoprecipitation + mass spectrometry; SIRT4 knockdown in INS-1E cells; insulin secretion assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — reconstitution of enzymatic activity in vitro, reciprocal co-IP/MS for interactors, functional KD phenotype, multiple orthogonal methods in one study\",\n      \"pmids\": [\"17715127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"mTORC1 promotes glutamine anaplerosis by activating GDH through transcriptional repression of SIRT4. Mechanistically, mTORC1 represses SIRT4 by promoting proteasome-mediated destabilization of the transcription factor CREB2, placing SIRT4 downstream of mTORC1 in a glutaminolysis regulatory pathway.\",\n      \"method\": \"mTORC1 activation/inhibition (rapamycin); CREB2 overexpression/knockdown; proteasome inhibitor treatment; SIRT4 mRNA/protein measurement; GDH activity assay; cell proliferation and transformation assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis established by genetic and pharmacological manipulation, multiple orthogonal methods, pathway placement confirmed\",\n      \"pmids\": [\"23663782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DNA damage induces SIRT4 expression, which represses glutamine metabolism (conversion of glutamine to TCA cycle intermediates), and this metabolic block is required for proper DNA damage response including cell cycle arrest. SIRT4 KO mice spontaneously develop lung tumors, establishing SIRT4 as a tumor suppressor that links the DNA damage response to glutamine metabolism.\",\n      \"method\": \"Genotoxic agent treatment; SIRT4 KO mouse model; glutamine metabolism flux assays; cell cycle analysis; genomic instability assays; tumor surveillance in KO mice\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse with spontaneous tumor phenotype, multiple genotoxic agents tested, metabolic flux assays, replicated across multiple stress conditions\",\n      \"pmids\": [\"23562301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SIRT4 deacetylates and inhibits malonyl CoA decarboxylase (MCD), an enzyme producing acetyl-CoA from malonyl-CoA. SIRT4 KO mice display elevated MCD activity and decreased malonyl-CoA in skeletal muscle and adipose tissue, leading to increased fatty acid oxidation and protection against diet-induced obesity.\",\n      \"method\": \"In vitro deacetylase assay of MCD; SIRT4 KO mouse metabolic phenotyping; malonyl-CoA measurement; fatty acid oxidation assays; exercise tolerance tests\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro enzymatic assay identifying MCD as substrate, KO mouse with defined metabolic phenotype, multiple tissues examined\",\n      \"pmids\": [\"23746352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SIRT4 represses fatty acid oxidation in the liver; SIRT4 null mice show increased PPARα target gene expression and higher rates of fatty acid oxidation in primary hepatocytes. The enhanced fatty acid oxidation in SIRT4 KO hepatocytes requires functional SIRT1, demonstrating cross-talk between mitochondrial SIRT4 and nuclear SIRT1.\",\n      \"method\": \"SIRT4 KO mouse; primary hepatocyte fatty acid oxidation assays; SIRT4 overexpression; SIRT1 inhibition in SIRT4 KO hepatocytes; PPARα target gene expression\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse + primary cells + genetic epistasis (SIRT1 required for SIRT4 KO phenotype), multiple orthogonal methods\",\n      \"pmids\": [\"24043310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SIRT4 overexpression represses Myc-induced B cell lymphomagenesis via inhibition of mitochondrial glutamine metabolism; SIRT4 loss in Eμ-Myc transgenic mice accelerates lymphomagenesis. SIRT4 overexpression dampens glutamine utilization even in Myc-driven Burkitt lymphoma cells and sensitizes them to glucose depletion.\",\n      \"method\": \"SIRT4 overexpression in human Burkitt lymphoma cells; Eμ-Myc/SIRT4-null mouse model; glutamine uptake measurement; GDH activity assay; survival analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic mouse model with tumor phenotype, in vitro mechanistic studies, GDH activity confirmation\",\n      \"pmids\": [\"24368766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SIRT4 regulates mitochondrial ATP homeostasis via the adenine nucleotide translocator ANT2; loss of SIRT4 decreases cellular ATP levels in vitro and in vivo, whereas SIRT4 overexpression increases ATP. SIRT4 loss activates a retrograde mitochondria-to-nucleus signaling response including AMPK, PGC1α, acetyl-CoA carboxylase, and mitochondrial respiratory machinery.\",\n      \"method\": \"SIRT4 KO and overexpression in cells and in vivo; ATP measurement; AMPK/PGC1α pathway readouts; retrograde signaling assays\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO and OE with defined ATP phenotype, AMPK pathway placement; ANT2 interaction mechanism inferred from prior co-IP data, not re-demonstrated here\",\n      \"pmids\": [\"24296486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"C. elegans SIRT4 orthologs SIR-2.2 and SIR-2.3 localize to mitochondria and function during oxidative stress. Both worm and mammalian SIRT4 interact with mitochondrial biotin-dependent carboxylases (pyruvate carboxylase PC, propionyl-CoA carboxylase PCC, methylcrotonyl-CoA carboxylase MCCC). The carboxylases are acetylated on multiple lysines; however, no changes in mPC acetylation or activity were detected upon SIRT4 overexpression or loss.\",\n      \"method\": \"Co-immunoprecipitation of SIRT4 with biotin-dependent carboxylases; mass spectrometry identification of acetylation sites; C. elegans oxidative stress assays; SIRT4 KO/OE acetylation analysis\",\n      \"journal\": \"Mitochondrion\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — co-IP identifies carboxylase interaction, negative result for PC acetylation regulation, single study\",\n      \"pmids\": [\"23438705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SIRT4 is a lysine deacylase that removes methylglutaryl (MG)-, hydroxymethylglutaryl (HMG)-, and 3-methylglutaconyl (MGc)-lysine modifications from substrates. These acyl marks are intermediates in leucine oxidation. SIRT4 controls leucine catabolism in mice, and dysregulated leucine metabolism in SIRT4 KO mice leads to elevated basal and stimulated insulin secretion, progressing to glucose intolerance and insulin resistance with age.\",\n      \"method\": \"Phylogenetic analysis; structural biology; in vitro enzymology with defined acyl-substrates; SIRT4 KO mouse metabolic phenotyping; insulin secretion and glucose tolerance assays\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted enzymatic activity in vitro with mutagenesis, structural biology, and KO mouse phenotype in one study\",\n      \"pmids\": [\"28380376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SIRT4 identified as the first cellular lipoamidase, removing lipoyl modifications from lysine residues of pyruvate dehydrogenase complex (PDH) subunits, thereby modulating PDH activity and acetyl-CoA production.\",\n      \"method\": \"In vitro lipoamidase assay; PDH activity measurement; identification via SIRT4 interaction proteomics\",\n      \"journal\": \"Methods in molecular biology (Clifton, N.J.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Weak — enzymatic activity described in methods/protocol paper citing prior findings; original experimental demonstration referenced but not fully detailed in this abstract\",\n      \"pmids\": [\"27246218\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SIRT4 physically interacts with OPA1 (the dynamin-related GTPase regulating inner mitochondrial membrane fusion) via co-immunoprecipitation. Moderate SIRT4 overexpression (enzymatically active but not H161Y mutant) increases long-form L-OPA1, promoting mitochondrial fusion and counteracting fission/mitophagy. Endogenous SIRT4 upregulation (via miR-15b inhibition or ionizing radiation) similarly increases L-OPA1 and fusion.\",\n      \"method\": \"Co-immunoprecipitation of SIRT4 and OPA1; SIRT4 overexpression including H161Y catalytic mutant; mitochondrial morphology imaging; mitophagy flux assays; miR-15b inhibitor treatment; ionizing radiation senescence model\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — co-IP of SIRT4-OPA1, enzymatic mutant controls, functional morphology readouts; single lab\",\n      \"pmids\": [\"29081403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SIRT4 inhibits mitochondrial fission in NSCLC cells by inhibiting Drp1 phosphorylation and weakening Drp1 recruitment to the mitochondrial membrane via interaction with Fis-1. SIRT4 expression also suppresses MEK/ERK activity, implicating the ERK-Drp1 pathway in SIRT4-mediated inhibition of cancer cell invasion and migration.\",\n      \"method\": \"SIRT4 plasmid transfection and siRNA in lung cancer cell lines; confocal microscopy for mitochondrial localization; phospho-Drp1 western blot; Drp1-Fis1 interaction assay; invasion/migration assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — multiple functional readouts, phosphorylation analysis, single lab\",\n      \"pmids\": [\"27941873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SIRT4 interacts with PTEN and promotes its degradation through the lysosomal pathway mediated by insulin-degrading enzyme (IDE). SIRT4 bridges PTEN and IDE for degradation in response to nutritional starvation. This regulation is independent of PTEN acetylation and ubiquitination. Induction of SIRT4 during nutrient starvation reduces PTEN levels to promote cell survival.\",\n      \"method\": \"Co-immunoprecipitation of SIRT4-PTEN and SIRT4-IDE; SIRT4 overexpression/knockdown; lysosome pathway inhibitors; ubiquitination/acetylation analysis; nutritional starvation stress model\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — co-IP of three-protein complex, lysosome pathway validation, single lab\",\n      \"pmids\": [\"30649986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SIRT4 inhibits the anaplerotic conversion of glutamine to α-ketoglutarate, which potentiates TORC1 signaling (retrograde mitochondria-to-nucleus signaling). SIRT4 is induced in the fed state and activates TORC1 while inhibiting AMPK-PGC1α/SIRT1-PPARα catabolic signaling, thereby regulating lipogenesis, autophagy, and cell proliferation.\",\n      \"method\": \"SIRT4 KO and overexpression; TORC1 activity assays; glutamine metabolism flux; AMPK and PPARα pathway measurements; fed/fasted state comparison\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO and OE with multiple pathway readouts, mechanistic epistasis established, single lab\",\n      \"pmids\": [\"31685549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PAK6 (a serine/threonine kinase) forms a complex with SIRT4 and ANT2 in the mitochondrial inner membrane. PAK6 promotes SIRT4 ubiquitin-mediated proteolysis. SIRT4 deacetylates ANT2 at K105, promoting its ubiquitination and degradation. Thus PAK6 adjusts ANT2 acetylation through the PAK6-SIRT4-ANT2 axis to regulate prostate cancer cell apoptosis.\",\n      \"method\": \"Co-immunoprecipitation of PAK6-SIRT4-ANT2; immunoelectron microscopy for PAK6 mitochondrial localization; ubiquitination assay; site-specific acetylation analysis of ANT2-K105; xenograft model; flow cytometry for apoptosis\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — reciprocal co-IP, site-specific modification identified, in vivo xenograft, single lab\",\n      \"pmids\": [\"32194820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SIRT4 elevates BCAA catabolism through activation of methylcrotonyl-CoA carboxylase (MCCC) during early adipogenesis, promoting BCAA flux and subsequent PPARγ activation and adipocyte differentiation.\",\n      \"method\": \"Metabolite consumption profiling during adipocyte differentiation; SIRT4 KO; MCCC activity assays; leucine oxidation measurement; PPARγ pathway readouts\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO with metabolic flux assays and MCCC activity measurement, pathway placement established, single lab\",\n      \"pmids\": [\"34260923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SIRT4 deacetylates MTHFD2 at lysine 50 (K50), destabilizing MTHFD2 via cullin 3 E3 ligase-mediated proteasomal degradation in response to folate deprivation stress. This suppresses NADPH production and leads to ROS accumulation, inhibiting breast cancer cell growth.\",\n      \"method\": \"In vitro deacetylation assay; site-directed mutagenesis of K50; cullin 3 ubiquitination assay; SIRT4 KO/OE; NADPH measurement; ROS measurement; folate deprivation stress model\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro enzymatic assay with site mutagenesis, ubiquitination confirmation, single lab\",\n      \"pmids\": [\"35349697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SIRT4 ADP-ribosylates MAT2A at glutamic acid 111, inhibiting its activity. In HCC, the mTORC1-c-Myc axis drives TRIM32-mediated degradation of SIRT4; loss of SIRT4 activates MAT2A, increasing S-adenosylmethionine (SAM) levels and promoting gene expression changes that support tumor proliferation.\",\n      \"method\": \"ADP-ribosylation assay of MAT2A; site identification (E111); TRIM32 ubiquitination assay; SIRT4 KO/OE; SAM metabolite measurement; mTORC1/c-Myc pathway analysis; xenograft and dietary methionine restriction models\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — enzymatic activity with substrate site identified, upstream degradation mechanism defined, single lab\",\n      \"pmids\": [\"36371321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SIRT4 translocates from mitochondria to the cytoplasm and then to the nucleus in response to TGF-β stimulation. In the nucleus, SIRT4 deacetylates U2AF2 at K413, facilitating splicing of CCN2 pre-mRNA and promoting CCN2 protein expression, thereby driving renal fibrosis. TGF-β activates ERK, inducing phosphorylation of SIRT4 at Ser36, promoting its interaction with importin α1 and nuclear translocation.\",\n      \"method\": \"TGF-β stimulation; SIRT4 nuclear fractionation; BAX/BAK pore inhibition; ERK pathway inhibition; phosphorylation of SIRT4 S36; importin α1 co-immunoprecipitation; SIRT4 deacetylation of U2AF2 K413; alternative splicing analysis; SIRT4 TEC-specific KO mouse; UUO fibrosis model\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mechanistic pathway from stimulus to nuclear translocation to substrate deacetylation defined by multiple orthogonal methods including KO mouse, phosphorylation site mapping, and splicing analysis\",\n      \"pmids\": [\"39495216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Upon Wnt stimulation, SIRT4 translocates from mitochondria to the cytoplasm where it deacetylates Axin1 at K147 (in the RGS domain). Deacetylation of Axin1-K147 impairs β-TrCP assembly into the destruction complex, leading to β-catenin accumulation and activation of canonical Wnt signaling.\",\n      \"method\": \"SIRT4 subcellular fractionation after Wnt stimulation; co-immunoprecipitation of SIRT4-Axin1; Axin1-K147R mutation; β-catenin accumulation assay; β-TrCP complex assembly assay; luciferase reporter for Wnt activity\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — site-specific mutagenesis of substrate, co-IP, functional pathway readout; single lab, SIRT4 deacylase activity assumed but not directly reconstituted in vitro\",\n      \"pmids\": [\"35707358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SIRT4 acts as a decarbamylase that removes carbamyl groups from ornithine transcarbamylase (OTC) at lysine 307 in an NAD+-dependent manner, inactivating OTC. Amino acid sufficiency downregulates SIRT4 expression (via suppression of the GCN2-eIF2α-ATF4 axis), allowing OTC K307 carbamylation to activate the urea cycle and detoxify ammonia. SIRT4 KO increases urea cycle activity and reduces blood ammonia.\",\n      \"method\": \"Proteomic/interactome screening; co-immunoprecipitation of SIRT4-OTC; in vitro decarbamylase assay; OTC K307 carbamylation measurement; GCN2-eIF2α-ATF4 pathway analysis; SIRT4 KO mouse; CCl4-hepatic encephalopathy model\",\n      \"journal\": \"Nature metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — novel enzymatic activity (decarbamylase) reconstituted in vitro with substrate site identified, KO mouse with in vivo phenotype, upstream regulatory pathway defined\",\n      \"pmids\": [\"37081161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SIRT4 deacetylates GNPAT (glyceronephosphate O-acyltransferase), regulating its acetylation and protein stability in the context of CSE-induced ferroptosis in COPD. GNPAT knockdown mitigated CSE-induced ferroptosis. SIRT4 overexpression suppresses ferroptosis; GNPAT overexpression reverses this inhibition.\",\n      \"method\": \"Immunoprecipitation for GNPAT acetylation; SIRT4 OE/KD; GNPAT KD; ROS/lipid ROS/GPX4 measurements; COPD mouse model with cigarette smoke; A549 cell CSE treatment\",\n      \"journal\": \"Respiratory research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — co-IP for acetylation, genetic epistasis via rescue experiment, single lab\",\n      \"pmids\": [\"38041059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SIRT4 deacetylates HSP60 to facilitate assembly of the HSP60-HSP10 complex, which maintains activity of mitochondrial ETC complexes II and III, sustaining ATP generation and reducing ROS in the context of burn sepsis. Glutamine activates SIRT4 by upregulating its synthesis and raising NAD+ levels.\",\n      \"method\": \"SIRT4 OE/KD; HSP60 acetylation measurement; HSP60-HSP10 complex assembly assay; ETC complex II/III activity; ATP and ROS measurement; NAD+ measurement; burn sepsis mouse model\",\n      \"journal\": \"Redox report\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — acetylation-dependent complex assembly demonstrated, functional ETC readout, single lab\",\n      \"pmids\": [\"38329114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SIRT4 downregulation in chondrocytes inhibits PINK1, impairing mitophagy and causing accumulation of ROS and damaged mitochondria, leading to chondrocyte senescence. SIRT4 overexpression rescues PINK1-mediated mitophagy and protects against TBHP-induced senescence. PINK1 overexpression counteracts the effects of SIRT4 knockdown.\",\n      \"method\": \"SIRT4 KD/OE in chondrocytes; PINK1 expression analysis; mitochondrial morphology/membrane potential/ROS/ATP measurement; PINK1 OE rescue experiment; OA mouse model; lentiviral gene therapy\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (PINK1 rescues SIRT4 KD), in vivo OA model, multiple mitochondrial readouts; single lab\",\n      \"pmids\": [\"38385071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SIRT4 directly deacetylates ENO1 (enolase 1) at K358, reducing ENO1's RNA-binding capacity while enhancing its glycolytic substrate 2-PG affinity and catalytic activity. This increases glycolytic flux and lactate production. Elevated lactate drives histone lactylation at H3K9 and H3K18, causing epigenetic reprogramming that activates stemness pathways in pancreatic tumor-initiating cells. SIRT4 expression is upregulated by α2δ1-mediated calcium signaling.\",\n      \"method\": \"SIRT4 OE/KD in pancreatic TICs; in vitro deacetylation of ENO1-K358; ENO1 mutant analysis (RNA binding and enzymatic activity); glycolytic flux measurement; lactate measurement; histone lactylation (H3K9lac, H3K18lac) ChIP; sphere formation and TIC assays; calcium channel manipulation\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro enzymatic assay with site mutagenesis, histone modification ChIP validation, single lab; novel context-dependent oncogenic role\",\n      \"pmids\": [\"40298941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CtBP directly represses SIRT4 gene expression at the transcriptional level in cancer cells, promoting glutaminolysis by allowing GDH activity to proceed unchecked; this coordinates glucose and glutamine metabolism. High glucose maintains CtBP dimerization and promoter binding to repress SIRT4, whereas low glucose abolishes CtBP binding to the SIRT4 promoter.\",\n      \"method\": \"CtBP knockdown/overexpression; SIRT4 promoter ChIP; CtBP dimerization inhibitor MTOB; GDH activity assay; glutamine consumption measurement; pH homeostasis assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for promoter binding, pharmacological and genetic manipulation, GDH activity confirmation; single lab\",\n      \"pmids\": [\"25633289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FOXQ1, a forkhead transcription factor, maintains SIRT4 expression in young cells. In senescence, FOXQ1 and SIRT4 expression decrease, leading to de-repression of GDH from SIRT4-mediated ADP-ribosylation. Elevated GDH activity increases α-ketoglutarate production, which drives histone demethylation (loss of H3K9me3) at IL-6 and IL-8 promoters, activating SASP.\",\n      \"method\": \"Transcription factor analysis; FOXQ1 and SIRT4 manipulations; GDH activity assay; α-KG measurement; H3K9me3 ChIP at IL-6/IL-8 promoters; GDH inhibitor treatment; senescence models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, enzymatic activity, genetic manipulations with pathway epistasis; single lab\",\n      \"pmids\": [\"37516739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FOXM1 binds to the SIRT4 promoter to induce its transcriptional activation; SIRT4 then suppresses NF-κB signaling and the NLRP3 inflammasome, protecting against podocyte pyroptosis in diabetic nephropathy. SIRT4 downregulation blocked FOXM1's protective effects.\",\n      \"method\": \"FOXM1 promoter binding assay (chromatin); SIRT4 OE/KD; NF-κB phosphorylation; NLRP3/caspase-1 expression; pyroptosis assay; diabetic mouse model\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — promoter binding confirmed, genetic epistasis (SIRT4 KD reverses FOXM1 effect), in vivo model; single lab\",\n      \"pmids\": [\"34626587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Lsd1 (lysine-specific demethylase 1) directly represses Sirt4 gene expression in trophoblast stem cells. Inactivation of Lsd1 causes Sirt4 upregulation, leading to decreased glutamine anaplerosis and mitochondrial function, triggering senescence. Sirt4 knockdown in Lsd1-deficient TSCs restores glutamine anaplerosis, redox balance, and mitochondrial function.\",\n      \"method\": \"Lsd1 deletion/inhibition; genome-wide transcriptional profiling; global metabolomics; Sirt4 knockdown rescue experiment; glutamine anaplerosis measurement; mitochondrial function assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis by double manipulation (Lsd1 KO + Sirt4 KD rescue), metabolomics, single lab\",\n      \"pmids\": [\"28230862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SIRT4 localizes to mitochondria within the brain, is highly expressed in astrocytes and radial glia (but not neurons). SIRT4 and GDH1 overexpression play antagonistic roles in regulating gliogenesis in radial glial cells: SIRT4 (via ADP-ribosylation and inhibition of GDH1) opposes GDH1-driven acceleration of glial development.\",\n      \"method\": \"Subcellular fractionation/immunofluorescence in brain tissue; SIRT4 and GDH1 overexpression in CTX8 radial glial cell line; gliogenesis assays\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — localization confirmed in brain cells, functional antagonism in gliogenesis established; single lab, mechanism inferred from GDH1 inhibition\",\n      \"pmids\": [\"23281078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Loss of SIRT4 leads to decreased expression and function of glutamate transporter GLT-1 in the brain, and increased sensitivity to kainic acid (excitotoxin). SIRT4 is upregulated in response to kainic acid treatment, suggesting a stress-responsive role in maintaining glutamate transport capacity.\",\n      \"method\": \"SIRT4 KO mouse; kainic acid treatment; GLT-1 expression and glutamate uptake assay; seizure severity measurement\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with defined transporter expression and function readouts, single lab\",\n      \"pmids\": [\"25196144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SIRT4 protects intestinal fibrosis by facilitating GLS1 (glutaminase 1) degradation; SIRT4 hinders SIRT5's stabilizing interaction with GLS1, promoting GLS1 degradation. This reduces glutaminolysis and decreases α-ketoglutarate, which limits KDM6-mediated H3K27me3 erasure at ECM gene promoters, thereby maintaining H3K27me3-dependent repression of ECM components.\",\n      \"method\": \"SIRT4 KO/OE; GLS1 stability assay; SIRT5-GLS1 interaction co-IP; SIRT4-SIRT5-GLS1 competition assay; α-KG measurement; H3K27me3 ChIP; ECM gene expression; intestinal fibrosis mouse model\",\n      \"journal\": \"Matrix biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — co-IP for protein interactions, histone modification ChIP, functional fibrosis model; single lab\",\n      \"pmids\": [\"37541633\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SIRT4 is a mitochondrially localized NAD+-dependent enzyme with multiple enzymatic activities — ADP-ribosyltransferase (targeting GDH to repress glutamine catabolism and insulin secretion), lysine deacylase removing MG/HMG/MGc acyl groups (regulating leucine catabolism), deacetylase (targeting MCD to control lipid metabolism, MTHFD2 and HSP60 to regulate folate metabolism and ETC assembly), lipoamidase (delipoylating PDH), and decarbamylase (inactivating OTC to regulate the urea cycle); under specific stimuli such as Wnt or TGF-β signaling, SIRT4 translocates from mitochondria to the cytoplasm or nucleus to deacetylate Axin1 (modulating Wnt/β-catenin signaling) or U2AF2 (modulating alternative splicing of CCN2 to drive fibrosis), respectively; SIRT4 is transcriptionally repressed by mTORC1 (via CREB2 destabilization), CtBP, and Lsd1, and is induced by DNA damage and genotoxic stress, placing it at the intersection of nutrient sensing, metabolic regulation, DNA damage response, and tumor suppression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SIRT4 is a mitochondrial-matrix NAD+-dependent enzyme that functions as a central node coupling amino acid and lipid metabolism to nutrient sensing, the DNA damage response, and tumor suppression [#0, #3]. Its founding activity is ADP-ribosylation of glutamate dehydrogenase (GDH), which represses glutamine/amino acid-stimulated insulin secretion in pancreatic beta cells and constrains glutamine anaplerosis into the TCA cycle [#0, #1]. Beyond ADP-ribosyltransferase activity, SIRT4 carries an unusually broad catalytic repertoire: it is a lysine deacylase that removes methylglutaryl, hydroxymethylglutaryl and 3-methylglutaconyl marks to control leucine catabolism [#9], a lipoamidase that delipoylates the pyruvate dehydrogenase complex [#10], and a decarbamylase that inactivates ornithine transcarbamylase at K307 to gate the urea cycle [#21]. As a deacetylase it targets malonyl-CoA decarboxylase to suppress fatty acid oxidation [#4], MTHFD2 (K50) to couple folate metabolism to redox balance [#17], and HSP60 to sustain electron transport chain complex assembly [#23]. Through repression of glutamine metabolism SIRT4 enforces cell-cycle arrest after genotoxic stress and restrains Myc-driven lymphomagenesis, and SIRT4-null mice spontaneously develop tumors [#3, #6]. SIRT4 expression is set by converging transcriptional and degradative controls: it is repressed by mTORC1 (via CREB2 destabilization), CtBP and Lsd1, induced by FOXM1, FOXQ1 and DNA damage, and degraded via PAK6 and TRIM32 [#2, #26, #29, #3, #18]. Under defined stimuli SIRT4 leaves the mitochondrion: TGF-\\u03b2-driven ERK phosphorylation at Ser36 promotes importin-\\u03b11-dependent nuclear import where SIRT4 deacetylates the splicing factor U2AF2 (K413) to drive CCN2 splicing and fibrosis [#19], and Wnt stimulation drives cytoplasmic deacetylation of Axin1 (K147) to activate \\u03b2-catenin signaling [#20]. SIRT4 also shapes mitochondrial dynamics and quality control, interacting with OPA1 to favor fusion and supporting PINK1-dependent mitophagy [#11, #24].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established SIRT4's founding biochemical activity and physiological output by showing it ADP-ribosylates GDH to repress amino acid-stimulated insulin secretion, defining a mitochondrial sirtuin acting on metabolism rather than chromatin.\",\n      \"evidence\": \"Loss-of-function in insulinoma cells and SIRT4 KO mice with phosphodiesterase sensitivity and GDH/insulin secretion assays\",\n      \"pmids\": [\"16959573\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the full substrate range beyond GDH\", \"ADP-ribosylation site on GDH not mapped\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Localized SIRT4 to the mitochondrial matrix with N-terminal processing, confirmed in vitro ADP-ribosyltransferase activity and absence of classical HDAC activity, and identified IDE and ANT2/ANT3 as interactors.\",\n      \"evidence\": \"Mitochondrial import/processing assay, in vitro enzymology, co-IP/MS, and SIRT4 knockdown in INS-1E cells\",\n      \"pmids\": [\"17715127\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of ANT/IDE interactions not established here\", \"Histone ADP-ribosylation in vitro of uncertain physiological relevance\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Placed SIRT4 within nutrient-sensing and tumor-suppression circuits: mTORC1 represses SIRT4 (via CREB2 destabilization) to license glutamine anaplerosis, while DNA damage induces SIRT4 to block glutamine metabolism and enforce cell-cycle arrest, with SIRT4-null mice developing tumors.\",\n      \"evidence\": \"Pharmacological/genetic mTORC1 and CREB2 manipulation; genotoxic treatment; SIRT4 KO mouse tumor surveillance; metabolic flux assays\",\n      \"pmids\": [\"23663782\", \"23562301\", \"24368766\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct enzymatic link between SIRT4 and cell-cycle machinery not defined\", \"Tissue specificity of tumor suppression incompletely mapped\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended SIRT4 beyond glutamine to lipid handling and energy homeostasis, identifying MCD as a deacetylation substrate that restrains fatty acid oxidation, demonstrating SIRT1-dependent cross-talk, and linking SIRT4 to ANT2-mediated ATP homeostasis and AMPK/PGC1\\u03b1 retrograde signaling.\",\n      \"evidence\": \"In vitro MCD deacetylase assay; SIRT4 KO metabolic phenotyping; primary hepatocyte FAO assays; SIRT1 epistasis; ATP and AMPK/PGC1\\u03b1 readouts\",\n      \"pmids\": [\"23746352\", \"24043310\", \"24296486\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ANT2 interaction inferred from prior co-IP, not re-demonstrated\", \"Mechanism of mitochondria-to-nucleus signaling not fully defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Reframed SIRT4 as a robust lysine deacylase by reconstituting removal of MG/HMG/MGc acyl marks (leucine-oxidation intermediates), connecting this activity to leucine catabolism and age-dependent glucose intolerance.\",\n      \"evidence\": \"Phylogenetics, structural biology, in vitro acyl-substrate enzymology with mutagenesis, and SIRT4 KO mouse metabolic phenotyping\",\n      \"pmids\": [\"28380376\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full set of endogenous deacylation substrates not enumerated\", \"Relative cellular contribution of deacylase vs ADP-ribosyltransferase activity unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Broadened SIRT4's catalytic repertoire to a lipoamidase that delipoylates PDH subunits, linking it directly to acetyl-CoA production, and documented carboxylase interactions without measurable acetylation regulation.\",\n      \"evidence\": \"In vitro lipoamidase assay and PDH activity measurement; co-IP of biotin-dependent carboxylases with negative acetylation result\",\n      \"pmids\": [\"27246218\", \"23438705\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Lipoamidase activity described in a methods paper citing prior work, not fully detailed\", \"Functional role of carboxylase binding unclear given absence of acetylation change\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Implicated SIRT4 in mitochondrial dynamics, showing enzymatically active SIRT4 interacts with OPA1 to favor fusion and inhibits Drp1-mediated fission via Fis1, restraining cancer cell invasion.\",\n      \"evidence\": \"Co-IP of SIRT4-OPA1 with H161Y catalytic mutant controls; phospho-Drp1 and Drp1-Fis1 assays; mitochondrial morphology and invasion readouts\",\n      \"pmids\": [\"29081403\", \"27941873\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether OPA1/Drp1 are direct enzymatic substrates not established\", \"Single-lab observations without independent replication\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed a non-catalytic scaffolding role in which SIRT4 bridges PTEN and IDE to drive lysosomal PTEN degradation during nutrient starvation, independent of PTEN modification.\",\n      \"evidence\": \"Co-IP of SIRT4-PTEN-IDE; lysosome inhibitors; ubiquitination/acetylation analysis; starvation stress model\",\n      \"pmids\": [\"30649986\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of complex assembly not structurally defined\", \"Single Co-IP-based three-protein complex without reconstitution\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved a context-dependent reversal of SIRT4-AMPK signaling, with SIRT4 induced in the fed state to potentiate TORC1 and suppress catabolic AMPK-PGC1\\u03b1/SIRT1-PPAR\\u03b1 programs, and defined a PAK6-SIRT4-ANT2 ubiquitination axis controlling apoptosis.\",\n      \"evidence\": \"SIRT4 KO/OE with TORC1, AMPK and PPAR\\u03b1 readouts; reciprocal PAK6-SIRT4-ANT2 co-IP, ANT2-K105 acetylation/ubiquitination, xenograft and apoptosis assays\",\n      \"pmids\": [\"31685549\", \"32194820\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reconciliation of fed-state TORC1 activation with mTORC1 repression of SIRT4 not fully integrated\", \"PAK6 axis demonstrated in single tumor context\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined SIRT4 nucleocytoplasmic translocation as a regulated signaling event, showing TGF-\\u03b2/ERK-driven Ser36 phosphorylation and importin-\\u03b11-dependent nuclear import enabling U2AF2-K413 deacetylation and pro-fibrotic CCN2 splicing, and Wnt-induced cytoplasmic Axin1-K147 deacetylation activating \\u03b2-catenin.\",\n      \"evidence\": \"Subcellular fractionation; S36 phospho-mapping; importin-\\u03b11 co-IP; U2AF2/Axin1 site-specific deacetylation and mutagenesis; splicing/\\u03b2-catenin readouts; TEC-specific KO and UUO models\",\n      \"pmids\": [\"39495216\", \"35707358\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of translocation across cell types and stimuli unknown\", \"Axin1 deacylase activity not directly reconstituted in vitro\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established additional enzymatic substrates linking SIRT4 to one-carbon, redox and methionine metabolism, with deacetylation of MTHFD2 (K50) triggering cullin3 degradation and ROS accumulation, and ADP-ribosylation of MAT2A (E111) controlling SAM levels downstream of mTORC1-c-Myc-TRIM32-mediated SIRT4 degradation.\",\n      \"evidence\": \"In vitro deacetylation/ADP-ribosylation with site mutagenesis; cullin3/TRIM32 ubiquitination assays; NADPH/ROS/SAM measurement; xenograft and dietary models\",\n      \"pmids\": [\"35349697\", \"36371321\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tissue specificity of these substrate relationships not broadly tested\", \"Single-lab findings\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified a fourth catalytic activity, NAD+-dependent decarbamylation of OTC at K307, integrating amino acid sufficiency (via GCN2-eIF2\\u03b1-ATF4 control of SIRT4) into urea-cycle regulation and ammonia detoxification.\",\n      \"evidence\": \"Interactome screening, SIRT4-OTC co-IP, in vitro decarbamylase assay, K307 carbamylation measurement, GCN2 axis analysis, KO mouse and CCl4 encephalopathy model\",\n      \"pmids\": [\"37081161\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether decarbamylation generalizes to other carbamylated proteins unknown\", \"Structural basis of the activity not solved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected SIRT4 to mitochondrial quality control and ferroptosis/fibrosis programs through deacetylation of HSP60 (ETC complex assembly), GNPAT (ferroptosis), GLS1 degradation via competition with SIRT5, and PINK1-dependent mitophagy.\",\n      \"evidence\": \"SIRT4 OE/KD with acetylation, complex assembly, ETC activity, ROS, PINK1 rescue, GLS1 stability and SIRT5 competition assays in disease models\",\n      \"pmids\": [\"38329114\", \"38041059\", \"37541633\", \"38385071\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect substrate relationships not all reconstituted in vitro\", \"Each role demonstrated in a single disease context and lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed a context-dependent oncogenic facet, with SIRT4 deacetylating ENO1 (K358) to favor glycolytic over RNA-binding function, raising lactate to drive histone lactylation and stemness in pancreatic tumor-initiating cells.\",\n      \"evidence\": \"In vitro ENO1-K358 deacetylation, mutant analysis, glycolytic flux/lactate measurement, H3K9/H3K18 lactylation ChIP and TIC assays\",\n      \"pmids\": [\"40298941\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reconciliation with established tumor-suppressor roles not resolved\", \"Single-lab, single tumor type\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SIRT4's multiple enzymatic activities are selectively engaged on specific substrates across tissues and stress states, and what governs the choice between mitochondrial metabolic versus extramitochondrial signaling functions, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model for activity/substrate selection\", \"Determinants of tumor-suppressive vs oncogenic outcomes undefined\", \"Structural basis for the diverse acyl/decarbamylase/ADP-ribosyl activities incomplete\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [4, 9, 10, 17, 19, 20, 21, 22, 23, 25]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 18]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [9, 10, 21]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [4, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 1, 8, 30]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [19]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [19, 20]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 4, 9, 21]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 6, 18, 25]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 14, 19, 20]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [19]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [24]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"GDH\", \"ANT2\", \"OPA1\", \"PTEN\", \"IDE\", \"PAK6\", \"U2AF2\", \"OTC\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}