Affinage

SIRT4

NAD-dependent protein lipoamidase sirtuin-4, mitochondrial · UniProt Q9Y6E7

Length
314 aa
Mass
35.2 kDa
Annotated
2026-06-10
100 papers in source corpus 33 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2006 High

    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

    PMID:16959573

    Open questions at the time
    • Did not resolve the full substrate range beyond GDH
    • ADP-ribosylation site on GDH not mapped
  2. 2007 High

    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

    PMID:17715127

    Open questions at the time
    • Functional consequence of ANT/IDE interactions not established here
    • Histone ADP-ribosylation in vitro of uncertain physiological relevance
  3. 2013 High

    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

    PMID:23562301 PMID:23663782 PMID:24368766

    Open questions at the time
    • Direct enzymatic link between SIRT4 and cell-cycle machinery not defined
    • Tissue specificity of tumor suppression incompletely mapped
  4. 2013 Medium

    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

    PMID:23746352 PMID:24043310 PMID:24296486

    Open questions at the time
    • ANT2 interaction inferred from prior co-IP, not re-demonstrated
    • Mechanism of mitochondria-to-nucleus signaling not fully defined
  5. 2017 High

    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

    PMID:28380376

    Open questions at the time
    • Full set of endogenous deacylation substrates not enumerated
    • Relative cellular contribution of deacylase vs ADP-ribosyltransferase activity unresolved
  6. 2016 Medium

    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

    PMID:23438705 PMID:27246218

    Open questions at the time
    • Lipoamidase activity described in a methods paper citing prior work, not fully detailed
    • Functional role of carboxylase binding unclear given absence of acetylation change
  7. 2017 Medium

    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

    PMID:27941873 PMID:29081403

    Open questions at the time
    • Whether OPA1/Drp1 are direct enzymatic substrates not established
    • Single-lab observations without independent replication
  8. 2019 Medium

    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

    PMID:30649986

    Open questions at the time
    • Mechanism of complex assembly not structurally defined
    • Single Co-IP-based three-protein complex without reconstitution
  9. 2020 Medium

    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

    PMID:31685549 PMID:32194820

    Open questions at the time
    • Reconciliation of fed-state TORC1 activation with mTORC1 repression of SIRT4 not fully integrated
    • PAK6 axis demonstrated in single tumor context
  10. 2022 High

    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

    PMID:35707358 PMID:39495216

    Open questions at the time
    • Generality of translocation across cell types and stimuli unknown
    • Axin1 deacylase activity not directly reconstituted in vitro
  11. 2022 Medium

    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

    PMID:35349697 PMID:36371321

    Open questions at the time
    • Tissue specificity of these substrate relationships not broadly tested
    • Single-lab findings
  12. 2023 High

    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

    PMID:37081161

    Open questions at the time
    • Whether decarbamylation generalizes to other carbamylated proteins unknown
    • Structural basis of the activity not solved
  13. 2023 Medium

    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

    PMID:37541633 PMID:38041059 PMID:38329114 PMID:38385071

    Open questions at the time
    • Direct vs indirect substrate relationships not all reconstituted in vitro
    • Each role demonstrated in a single disease context and lab
  14. 2025 Medium

    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

    PMID:40298941

    Open questions at the time
    • Reconciliation with established tumor-suppressor roles not resolved
    • Single-lab, single tumor type

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 10 GO:0016740 transferase activity 3 GO:0016787 hydrolase activity 3
Localization
GO:0005739 mitochondrion 4 GO:0005829 cytosol 2 GO:0005634 nucleus 1
Pathway
R-HSA-1430728 Metabolism 4 R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4 R-HSA-8953854 Metabolism of RNA 1 R-HSA-9612973 Autophagy 1
Partners
ANT2GDHIDEOPA1OTCPAK6PTENU2AF2

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 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. Loss-of-function in insulinoma cells and SIRT4 KO mice; phosphodiesterase sensitivity assay; GDH activity assay; insulin secretion measurement Cell High 16959573
2007 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. Mitochondrial import/processing assay; in vitro ADP-ribosyltransferase assay; co-immunoprecipitation + mass spectrometry; SIRT4 knockdown in INS-1E cells; insulin secretion assay The Journal of biological chemistry High 17715127
2013 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. mTORC1 activation/inhibition (rapamycin); CREB2 overexpression/knockdown; proteasome inhibitor treatment; SIRT4 mRNA/protein measurement; GDH activity assay; cell proliferation and transformation assays Cell High 23663782
2013 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. Genotoxic agent treatment; SIRT4 KO mouse model; glutamine metabolism flux assays; cell cycle analysis; genomic instability assays; tumor surveillance in KO mice Cancer cell High 23562301
2013 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. In vitro deacetylase assay of MCD; SIRT4 KO mouse metabolic phenotyping; malonyl-CoA measurement; fatty acid oxidation assays; exercise tolerance tests Molecular cell High 23746352
2013 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. SIRT4 KO mouse; primary hepatocyte fatty acid oxidation assays; SIRT4 overexpression; SIRT1 inhibition in SIRT4 KO hepatocytes; PPARα target gene expression Molecular and cellular biology High 24043310
2013 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. SIRT4 overexpression in human Burkitt lymphoma cells; Eμ-Myc/SIRT4-null mouse model; glutamine uptake measurement; GDH activity assay; survival analysis The Journal of biological chemistry High 24368766
2013 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. SIRT4 KO and overexpression in cells and in vivo; ATP measurement; AMPK/PGC1α pathway readouts; retrograde signaling assays Aging Medium 24296486
2013 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. Co-immunoprecipitation of SIRT4 with biotin-dependent carboxylases; mass spectrometry identification of acetylation sites; C. elegans oxidative stress assays; SIRT4 KO/OE acetylation analysis Mitochondrion Medium 23438705
2017 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. Phylogenetic analysis; structural biology; in vitro enzymology with defined acyl-substrates; SIRT4 KO mouse metabolic phenotyping; insulin secretion and glucose tolerance assays Cell metabolism High 28380376
2016 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. In vitro lipoamidase assay; PDH activity measurement; identification via SIRT4 interaction proteomics Methods in molecular biology (Clifton, N.J.) Medium 27246218
2017 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. 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 Aging Medium 29081403
2016 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. 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 Oncogene Medium 27941873
2019 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. Co-immunoprecipitation of SIRT4-PTEN and SIRT4-IDE; SIRT4 overexpression/knockdown; lysosome pathway inhibitors; ubiquitination/acetylation analysis; nutritional starvation stress model FASEB journal Medium 30649986
2020 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. SIRT4 KO and overexpression; TORC1 activity assays; glutamine metabolism flux; AMPK and PPARα pathway measurements; fed/fasted state comparison Molecular and cellular biology Medium 31685549
2020 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. 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 Theranostics Medium 32194820
2021 SIRT4 elevates BCAA catabolism through activation of methylcrotonyl-CoA carboxylase (MCCC) during early adipogenesis, promoting BCAA flux and subsequent PPARγ activation and adipocyte differentiation. Metabolite consumption profiling during adipocyte differentiation; SIRT4 KO; MCCC activity assays; leucine oxidation measurement; PPARγ pathway readouts Cell reports Medium 34260923
2022 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. 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 of molecular cell biology Medium 35349697
2022 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. 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 Cell & bioscience Medium 36371321
2022 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. 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 eLife High 39495216
2022 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. 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 Frontiers in oncology Medium 35707358
2023 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. 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 Nature metabolism High 37081161
2023 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. Immunoprecipitation for GNPAT acetylation; SIRT4 OE/KD; GNPAT KD; ROS/lipid ROS/GPX4 measurements; COPD mouse model with cigarette smoke; A549 cell CSE treatment Respiratory research Medium 38041059
2024 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. 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 Redox report Medium 38329114
2024 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. 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 International journal of biological sciences Medium 38385071
2025 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. 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 Advanced science Medium 40298941
2015 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. CtBP knockdown/overexpression; SIRT4 promoter ChIP; CtBP dimerization inhibitor MTOB; GDH activity assay; glutamine consumption measurement; pH homeostasis assays Cell death & disease Medium 25633289
2017 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. 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 Cell death & disease Medium 37516739
2021 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. FOXM1 promoter binding assay (chromatin); SIRT4 OE/KD; NF-κB phosphorylation; NLRP3/caspase-1 expression; pyroptosis assay; diabetic mouse model Experimental cell research Medium 34626587
2017 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. Lsd1 deletion/inhibition; genome-wide transcriptional profiling; global metabolomics; Sirt4 knockdown rescue experiment; glutamine anaplerosis measurement; mitochondrial function assays Cell death & disease Medium 28230862
2012 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. Subcellular fractionation/immunofluorescence in brain tissue; SIRT4 and GDH1 overexpression in CTX8 radial glial cell line; gliogenesis assays Glia Medium 23281078
2014 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. SIRT4 KO mouse; kainic acid treatment; GLT-1 expression and glutamate uptake assay; seizure severity measurement Journal of neurochemistry Medium 25196144
2019 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. 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 Matrix biology Medium 37541633

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. Cell 976 16959573
2013 The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4. Cell 471 23663782
2013 SIRT4 has tumor-suppressive activity and regulates the cellular metabolic response to DNA damage by inhibiting mitochondrial glutamine metabolism. Cancer cell 369 23562301
2007 Regulation of insulin secretion by SIRT4, a mitochondrial ADP-ribosyltransferase. The Journal of biological chemistry 332 17715127
2013 SIRT4 coordinates the balance between lipid synthesis and catabolism by repressing malonyl CoA decarboxylase. Molecular cell 298 23746352
2017 SIRT4 Is a Lysine Deacylase that Controls Leucine Metabolism and Insulin Secretion. Cell metabolism 263 28380376
2019 UHRF1 promotes aerobic glycolysis and proliferation via suppression of SIRT4 in pancreatic cancer. Cancer letters 135 30905812
2013 SIRT4 regulates ATP homeostasis and mediates a retrograde signaling via AMPK. Aging 133 24296486
2015 Tumour-suppressive function of SIRT4 in human colorectal cancer. British journal of cancer 128 26086877
2013 SIRT4 represses peroxisome proliferator-activated receptor α activity to suppress hepatic fat oxidation. Molecular and cellular biology 122 24043310
2017 SIRT4 interacts with OPA1 and regulates mitochondrial quality control and mitophagy. Aging 119 29081403
2016 MicroRNA-15b regulates mitochondrial ROS production and the senescence-associated secretory phenotype through sirtuin 4/SIRT4. Aging 113 26959556
2016 SIRT4 inhibits malignancy progression of NSCLCs, through mitochondrial dynamics mediated by the ERK-Drp1 pathway. Oncogene 111 27941873
2013 SIRT4 protein suppresses tumor formation in genetic models of Myc-induced B cell lymphoma. The Journal of biological chemistry 95 24368766
2020 Exosomal miRNA-320a Is Released from hAMSCs and Regulates SIRT4 to Prevent Reactive Oxygen Species Generation in POI. Molecular therapy. Nucleic acids 93 32506013
2013 SIRT4 prevents hypoxia-induced apoptosis in H9c2 cardiomyoblast cells. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 91 24029877
2020 Sirt4: A Multifaceted Enzyme at the Crossroads of Mitochondrial Metabolism and Cancer. Frontiers in oncology 66 32373514
2019 SIRT4 silencing in tumor-associated macrophages promotes HCC development via PPARδ signalling-mediated alternative activation of macrophages. Journal of experimental & clinical cancer research : CR 66 31744516
2018 SIRT4 is essential for metabolic control and meiotic structure during mouse oocyte maturation. Aging cell 65 29845740
2014 SIRT3 and SIRT4 are mitochondrial tumor suppressor proteins that connect mitochondrial metabolism and carcinogenesis. Cancer & metabolism 64 25332769
2018 Molecular link between glucose and glutamine consumption in cancer cells mediated by CtBP and SIRT4. Oncogenesis 59 29540733
2006 Insulin secretion: SIRT4 gets in on the act. Cell 59 16959562
2021 FOXM1-activated SIRT4 inhibits NF-κB signaling and NLRP3 inflammasome to alleviate kidney injury and podocyte pyroptosis in diabetic nephropathy. Experimental cell research 58 34626587
2019 SIRT4 and Its Roles in Energy and Redox Metabolism in Health, Disease and During Exercise. Frontiers in physiology 58 31447696
2016 SIRT4 overexpression protects against diabetic nephropathy by inhibiting podocyte apoptosis. Experimental and therapeutic medicine 58 28123512
2015 SIRT4 Suppresses Inflammatory Responses in Human Umbilical Vein Endothelial Cells. Cardiovascular toxicology 57 25331589
2019 Mitochondrial Function, Metabolic Regulation, and Human Disease Viewed through the Prism of Sirtuin 4 (SIRT4) Functions. Journal of proteome research 55 30913880
2015 CtBP maintains cancer cell growth and metabolic homeostasis via regulating SIRT4. Cell death & disease 55 25633289
2016 SIRT4 regulates cancer cell survival and growth after stress. Biochemical and biophysical research communications 52 26775843
2021 SIRT4 is an early regulator of branched-chain amino acid catabolism that promotes adipogenesis. Cell reports 51 34260923
2012 Glutamate dehydrogenase 1 and SIRT4 regulate glial development. Glia 51 23281078
2010 Calorie restriction on insulin resistance and expression of SIRT1 and SIRT4 in rats. Biochemistry and cell biology = Biochimie et biologie cellulaire 51 20651844
2020 Mitochondrial PAK6 inhibits prostate cancer cell apoptosis via the PAK6-SIRT4-ANT2 complex. Theranostics 48 32194820
2015 Sirtuin-4 (SIRT4) is downregulated and associated with some clinicopathological features in gastric adenocarcinoma. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 48 26054687
2014 Loss of SIRT4 decreases GLT-1-dependent glutamate uptake and increases sensitivity to kainic acid. Journal of neurochemistry 46 25196144
2018 SIRT4 acts as a tumor suppressor in gastric cancer by inhibiting cell proliferation, migration, and invasion. OncoTargets and therapy 44 30022839
2020 Loss of SIRT4 promotes the self-renewal of Breast Cancer Stem Cells. Theranostics 43 32863939
2019 SIRT4 inhibits the proliferation, migration, and invasion abilities of thyroid cancer cells by inhibiting glutamine metabolism. OncoTargets and therapy 43 30992675
2017 Inactivation of Lsd1 triggers senescence in trophoblast stem cells by induction of Sirt4. Cell death & disease 42 28230862
2016 MicroRNA-497 Inhibits Cardiac Hypertrophy by Targeting Sirt4. PloS one 41 27992564
2022 SIRT4 Suppresses Doxorubicin-Induced Cardiotoxicity by Regulating the AKT/mTOR/Autophagy Pathway. Toxicology 40 35134463
2019 SIRT4 suppresses the PI3K/Akt/NF‑κB signaling pathway and attenuates HUVEC injury induced by oxLDL. Molecular medicine reports 40 31059091
2014 SIRT4 inhibits cigarette smoke extracts-induced mononuclear cell adhesion to human pulmonary microvascular endothelial cells via regulating NF-κB activity. Toxicology letters 39 24603126
2024 Sirtuin 4 (Sirt4) downregulation contributes to chondrocyte senescence and osteoarthritis via mediating mitochondrial dysfunction. International journal of biological sciences 37 38385071
2020 EX-527 Prevents the Progression of High-Fat Diet-Induced Hepatic Steatosis and Fibrosis by Upregulating SIRT4 in Zucker Rats. Cells 37 32365537
2020 SIRT4 suppresses the inflammatory response and oxidative stress in osteoarthritis. American journal of translational research 35 32509191
2013 Sirt4: the glutamine gatekeeper. Cancer cell 35 23597559
2019 SIRT4 regulates PTEN stability through IDE in response to cellular stresses. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 33 30649986
2016 Molecular modeling, dynamics studies and density functional theory approaches to identify potential inhibitors of SIRT4 protein from Homo sapiens : a novel target for the treatment of type 2 diabetes. Journal of biomolecular structure & dynamics 33 27800715
2021 VHL regulates the sensitivity of clear cell renal cell carcinoma to SIRT4-mediated metabolic stress via HIF-1α/HO-1 pathway. Cell death & disease 32 34135317
2020 Anabolic SIRT4 Exerts Retrograde Control over TORC1 Signaling by Glutamine Sparing in the Mitochondria. Molecular and cellular biology 32 31685549
2020 HIF-1α-dependent miR-424 induction confers cisplatin resistance on bladder cancer cells through down-regulation of pro-apoptotic UNC5B and SIRT4. Journal of experimental & clinical cancer research : CR 32 32522234
2019 SIRT4 enhances the sensitivity of ER-positive breast cancer to tamoxifen by inhibiting the IL-6/STAT3 signal pathway. Cancer medicine 32 31573734
2022 mTORC1-c-Myc pathway rewires methionine metabolism for HCC progression through suppressing SIRT4 mediated ADP ribosylation of MAT2A. Cell & bioscience 31 36371321
2017 SIRT4 Is a Regulator of Insulin Secretion. Cell chemical biology 31 28644956
2020 Functions of mammalian SIRT4 in cellular metabolism and research progress in human cancer. Oncology letters 30 32774484
2024 The Role of Mitochondrial Sirtuins (SIRT3, SIRT4 and SIRT5) in Renal Cell Metabolism: Implication for Kidney Diseases. International journal of molecular sciences 29 39000044
2009 Fluorescence in situ hybridization and chromosomal organization of the sirtuin 4 gene (Sirt4) in the mouse. Biochemical and biophysical research communications 29 19306844
2023 Sirt4 deficiency promotes the development of atherosclerosis by activating the NF-κB/IκB/CXCL2/3 pathway. Atherosclerosis 28 37121164
2023 MiR-15b-5p and PCSK9 inhibition reduces lipopolysaccharide-induced endothelial dysfunction by targeting SIRT4. Cellular & molecular biology letters 28 37587410
2020 SIRT4 prevents excitotoxicity via modulating glutamate metabolism in glioma cells. Human & experimental toxicology 28 32081049
2018 Overexpression of SIRT4 inhibits the proliferation of gastric cancer cells through cell cycle arrest. Oncology letters 26 30745932
2023 The PIK3CA-E545K-SIRT4 signaling axis reduces radiosensitivity by promoting glutamine metabolism in cervical cancer. Cancer letters 25 36646410
2023 Amino acids downregulate SIRT4 to detoxify ammonia through the urea cycle. Nature metabolism 24 37081161
2024 Glutamine sustains energy metabolism and alleviates liver injury in burn sepsis by promoting the assembly of mitochondrial HSP60-HSP10 complex via SIRT4 dependent protein deacetylation. Redox report : communications in free radical research 23 38329114
2021 miRNA-130b-5p promotes hepatic stellate cell activation and the development of liver fibrosis by suppressing SIRT4 expression. Journal of cellular and molecular medicine 23 34272822
2018 Study of expression analysis of SIRT4 and the coordinate regulation of bovine adipocyte differentiation by SIRT4 and its transcription factors. Bioscience reports 23 30442871
2022 Coenzyme Q10 Supplement Rescues Postovulatory Oocyte Aging by Regulating SIRT4 Expression. Current molecular pharmacology 22 33881976
2022 miR-15a-5p enhances the malignant phenotypes of colorectal cancer cells through the STAT3/TWIST1 and PTEN/AKT signaling pathways by targeting SIRT4. Cellular signalling 22 36332797
2023 CSE triggers ferroptosis via SIRT4-mediated GNPAT deacetylation in the pathogenesis of COPD. Respiratory research 21 38041059
2022 Deacetylation of MTHFD2 by SIRT4 senses stress signal to inhibit cancer cell growth by remodeling folate metabolism. Journal of molecular cell biology 21 35349697
2022 SIRT4 Expression Ameliorates the Detrimental Effect of Heat Stress via AMPK/mTOR Signaling Pathway in BMECs. International journal of molecular sciences 21 36362094
2021 SIRT4 is the molecular switch mediating cellular proliferation in colorectal cancer through GLS mediated activation of AKT/GSK3β/CyclinD1 pathway. Carcinogenesis 21 33315089
2019 Recovery of Olfactory Function After Excitotoxic Lesion of the Olfactory Bulbs Is Associated with Increases in Bulbar SIRT1 and SIRT4 Expressions. Molecular neurobiology 21 30661205
2018 Knockout of SIRT4 decreases chemosensitivity to 5-FU in colorectal cancer cells. Oncology letters 20 30008852
2013 Mitochondrial SIRT4-type proteins in Caenorhabditis elegans and mammals interact with pyruvate carboxylase and other acetylated biotin-dependent carboxylases. Mitochondrion 20 23438705
2025 SIRT4 Promotes Pancreatic Cancer Stemness by Enhancing Histone Lactylation and Epigenetic Reprogramming Stimulated by Calcium Signaling. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 19 40298941
2020 miR-424-5p regulates cell proliferation and migration of esophageal squamous cell carcinoma by targeting SIRT4. Journal of Cancer 19 33033517
2024 Sodium butyrate blocks the growth of colorectal cancer by inhibiting the aerobic glycolysis mediated by SIRT4/HIF-1α. Chemico-biological interactions 18 39241941
2023 Cisplatin-induced PANDAR-Chemo-EVs contribute to a more aggressive and chemoresistant ovarian cancer phenotype through the SRSF9-SIRT4/SIRT6 axis. Journal of gynecologic oncology 17 37921598
2017 L-leucine stimulates glutamate dehydrogenase activity and glutamate synthesis by regulating mTORC1/SIRT4 pathway in pig liver. Animal nutrition (Zhongguo xu mu shou yi xue hui) 17 30175263
2023 SIRT4 protects against intestinal fibrosis by facilitating GLS1 degradation. Matrix biology : journal of the International Society for Matrix Biology 16 37541633
2018 Tumor-suppressive function of SIRT4 in neuroblastoma through mitochondrial damage. Cancer management and research 16 30519106
2022 SIRT4 functions as a tumor suppressor during prostate cancer by inducing apoptosis and inhibiting glutamine metabolism. Scientific reports 15 35842463
2017 Decreased SIRT4 protein levels in endometrioid adenocarcinoma tissues are associated with advanced AJCC stage. Cancer biomarkers : section A of Disease markers 15 28582846
2023 SIRT4 in ageing. Biogerontology 14 37067687
2023 Epigenetic activation of secretory phenotypes in senescence by the FOXQ1-SIRT4-GDH signaling. Cell death & disease 14 37516739
2022 SIRT4-Catalyzed Deacetylation of Axin1 Modulates the Wnt/β-Catenin Signaling Pathway. Frontiers in oncology 14 35707358
2018 DNA Methylation and Transcription Factors Competitively Regulate SIRT4 Promoter Activity in Bovine Adipocytes: Roles of NRF1 and CMYB. DNA and cell biology 14 30570339
2017 SIRT4 is upregulated in breast cancer and promotes the proliferation, migration and invasion of breast cancer cells. International journal of clinical and experimental pathology 14 31966549
2024 SIRT4 promotes neuronal apoptosis in models of Alzheimer's disease via the STAT2-SIRT4-mTOR pathway. American journal of physiology. Cell physiology 13 38586875
2023 SIRT4 is a regulator of human skeletal muscle fatty acid metabolism influencing inner and outer mitochondrial membrane-mediated fusion. Cellular signalling 13 37858614
2020 Nuclear factor E2 related factor (NRF2) inhibits mast cell- mediated allergic inflammation via SIRT4-mediated mitochondrial metabolism. Annals of palliative medicine 13 33222465
2016 Identification of Sirtuin4 (SIRT4) Protein Interactions: Uncovering Candidate Acyl-Modified Mitochondrial Substrates and Enzymatic Regulators. Methods in molecular biology (Clifton, N.J.) 13 27246218
2020 Mammalian SIRT4 is a tumor suppressor of clear cell renal cell carcinoma by inhibiting cancer proliferation, migration and invasion. Cancer biomarkers : section A of Disease markers 12 32675395
2024 Nuclear translocation of SIRT4 mediates deacetylation of U2AF2 to modulate renal fibrosis through alternative splicing-mediated upregulation of CCN2. eLife 11 39495216
2022 SIRT4 Is Highly Expressed in Retinal Müller Glial Cells. Frontiers in neuroscience 11 35185463
2018 Differential expressions of SIRT1, SIRT3, and SIRT4 in peripheral blood mononuclear cells from patients with type 2 diabetic retinopathy. Archives of physiology and biochemistry 11 30572719
2017 Novel role of the SIRT4-OPA1 axis in mitochondrial quality control. Cell stress 11 31225445
2015 A SIRT4-like auto ADP-ribosyltransferase is essential for the environmental growth of Mycobacterium smegmatis. Acta biochimica et biophysica Sinica 11 26685303

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