Affinage

SIRT2

NAD-dependent protein deacetylase sirtuin-2 · UniProt Q8IXJ6

Length
389 aa
Mass
43.2 kDa
Annotated
2026-06-10
100 papers in source corpus 53 papers cited in narrative 52 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SIRT2 is an NAD+-dependent lysine deacetylase that controls cell-cycle progression, metabolism, genome maintenance, cytoskeletal dynamics, and innate immunity through site-specific deacetylation of a broad substrate repertoire (PMID:22014574, PMID:27197174, PMID:33789098). In mitosis and meiosis it deacetylates the APC/C coactivators CDH1 and CDC20—loss of which elevates Aurora-A/-B and causes centrosome amplification and aneuploidy—and deacetylates BubR1 to stabilize it and support spindle assembly checkpoint fidelity, with declining NAD+ reducing this activity during aging (PMID:22014574, PMID:24825348, PMID:29067790). A major arm of its function is metabolic control: SIRT2 deacetylates and activates glycolytic and NADPH-generating enzymes including PKM2 (promoting active tetramer formation), PGAM2, G6PD, and IDH1, regulates hepatic and β-cell glucose handling via GKRP deacetylation, and broadly restrains T-cell metabolic reprogramming (PMID:24786789, PMID:27197174, PMID:27586085, PMID:29296001, PMID:32141187, PMID:32768387, PMID:33754030). SIRT2 enforces genome integrity by promoting BRCA1-BARD1 heterodimerization through deacetylation of the BARD1 RING domain and by facilitating homologous recombination and OGG1-dependent base excision repair, the latter potentiated by ATM/ATR phosphorylation at S46/S53 (PMID:33789098, PMID:38554113, PMID:33624391). It also deacetylates substrates governing cardiac homeostasis (LKB1-AMPK signaling, NFATc2, STAT3, NRF2), neuronal function (APP processing, AMPAR trafficking, α-tubulin), and innate immunity, where it deacetylates G3BP1 to disassemble the cGAS-G3BP1 complex and dampen cGAS-STING signaling (PMID:28793258, PMID:28947430, PMID:29440391, PMID:35830807, PMID:37870259, PMID:37783815, PMID:37728319). Beyond canonical deacetylation, SIRT2 acts as a defatty-acylase, removing myristoyl groups from K-Ras4a and RalB to regulate their membrane localization and transforming activity, and serves as a histone de-methacrylase (PMID:34961760, PMID:30734528, PMID:31433161). SIRT2 activity and stability are tuned by post-translational control, including ERK1/2-mediated stabilization, c-Src phosphorylation at Y104, SUMOylation, and PPM1A/PPM1B-mediated S25 dephosphorylation that triggers its relocalization from cytoplasm to chromatin during bacterial infection (PMID:29694890, PMID:23806683, PMID:24996174, PMID:33316537).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2007 High

    Established SIRT2 as a deacetylase that regulates a transcription factor's localization, linking it to differentiation programs and defining a core mode of action beyond histones.

    Evidence Co-IP and gain/loss-of-function in 3T3-L1 adipocytes showing FOXO1 deacetylation and altered nuclear/cytosolic shuttling

    PMID:17681146

    Open questions at the time
    • Specific lysine sites on FOXO1 not mapped
    • Relationship between deacetylation and insulin-stimulated phosphorylation not fully resolved
  2. 2011 High

    Defined SIRT2's role in mitotic fidelity by showing it deacetylates APC/C coactivators, establishing a tumor-suppressor function against aneuploidy.

    Evidence Mouse knockout with deacetylation assays and mitotic phenotyping of CDH1/CDC20

    PMID:22014574

    Open questions at the time
    • Acetylation sites on CDH1/CDC20 not specified
    • Direct effect on APC/C catalytic activity inferred from substrate levels
  3. 2013 Medium

    Connected SIRT2 to NF-κB transcriptional output and microtubule biology, broadening its substrate range to signaling and cytoskeletal targets.

    Evidence ChIP and acetylation assays for p65-K310/miR-21 in glioma; siRNA and confocal microscopy for α-tubulin/H4K16 in oocytes

    PMID:24161395 PMID:24334550

    Open questions at the time
    • Tissue-specificity of p65 regulation unclear
    • Direct vs indirect effects on tubulin acetylation not fully separated
  4. 2014 Medium

    Demonstrated SIRT2's metabolic enzyme regulation and its own upstream control, showing it activates PGAM2 and targets HIF-1α for degradation while being stabilized by ERK1/2 and destabilized by c-Src phosphorylation.

    Evidence In vitro deacetylation with active-site mutants (PGAM2-K100, HIF-1α-K709); Co-IP and kinase inhibitor/mutagenesis studies for ERK1/2 and c-Src-Y104

    PMID:23806683 PMID:24681946 PMID:24786789 PMID:24996174

    Open questions at the time
    • Integration of opposing ERK and Src inputs on a single SIRT2 pool unresolved
    • Physiological stimuli controlling these PTMs not fully defined
  5. 2014 High

    Linked SIRT2-mediated BubR1 deacetylation to organismal lifespan, establishing the NAD+-SIRT2-BubR1 axis as an aging-relevant node.

    Evidence In vivo overexpression and NMN treatment with site-specific acetylation mapping and lifespan measurement in BubR1 hypomorphic mice

    PMID:24825348

    Open questions at the time
    • Whether BubR1 stabilization fully accounts for lifespan effects unclear
    • CBP/SIRT2 competition kinetics not quantified
  6. 2016 High

    Cemented SIRT2 as a master regulator of glycolytic flux by showing it controls enzyme oligomerization and activity (PKM2, G6PD), reprogramming cancer metabolism.

    Evidence Mass spectrometry site mapping, tetramerization and enzymatic activity assays, metabolic flux analysis, and xenograft models

    PMID:27197174 PMID:27586085

    Open questions at the time
    • Context-dependence across tumor types not delineated
    • Net metabolic output integrating multiple enzyme targets not modeled
  7. 2017 High

    Extended SIRT2 function into cardiac protection, synaptic plasticity, and oligodendrocyte biology, showing deacetylation of LKB1, AMPARs, and regulation of myelination programs.

    Evidence Knockout mice, site-specific deacetylation/ubiquitination assays, electrophysiology and behavior; RNA pulldown for QKI-mediated Sirt2 mRNA stabilization

    PMID:28188285 PMID:28793258 PMID:28947430

    Open questions at the time
    • Cross-talk between metabolic and trafficking substrates in single cell types unresolved
    • How tissue-specific substrate selection is achieved unclear
  8. 2018 High

    Resolved a spatial-regulation mechanism—S25 dephosphorylation by PPM1A/PPM1B drives SIRT2 chromatin relocalization—and expanded metabolic and hypertrophy roles (GKRP, NFATc2).

    Evidence Phosphoproteomics with S25 mutagenesis and subcellular fractionation during Listeria infection; Co-IP, glucose tolerance tests, and KO mouse hypertrophy models

    PMID:29296001 PMID:29440391 PMID:29694890

    Open questions at the time
    • Signals coupling infection to phosphatase activation incompletely defined
    • Genome-wide chromatin targets of relocalized SIRT2 not catalogued
  9. 2019 High

    Identified SIRT2 as a defatty-acylase, revealing a non-deacetylase enzymatic activity that controls Ras-family GTPase membrane targeting.

    Evidence In vitro deacylation assays with site-specific mutagenesis and membrane localization/effector recruitment assays for K-Ras4a and RalB

    PMID:30734528 PMID:31433161

    Open questions at the time
    • Relative cellular contribution of deacylase vs deacetylase activity unquantified
    • Acyl-substrate spectrum incompletely mapped
  10. 2020 High

    Established SIRT2 as an immunometabolic brake and uncovered SUMOylation as a determinant of its tumor-suppressor substrate selection.

    Evidence Sirt2 KO T-cell metabolomics and Seahorse flux; SUMO-site mutagenesis with p38 deacetylation assays and xenografts; IDH1-K224 deacetylation studies

    PMID:32141187 PMID:32768387 PMID:33316537

    Open questions at the time
    • Mechanism by which SUMOylation redirects substrate choice unclear
    • In vivo immunometabolic targets in human T cells not fully defined
  11. 2021 High

    Defined SIRT2's direct role in DNA repair through BRCA1-BARD1 heterodimerization and HR/RAD51 recruitment, integrating it into genome-stability machinery.

    Evidence Co-IP, BARD1 RING-domain deacetylation mutagenesis, HR reporter and foci assays; GARS-mediated SIRT2 inhibition with Drosophila rescue; C/EBPβ deacetylation-ubiquitination studies

    PMID:33624391 PMID:33789098 PMID:34053152 PMID:34642310

    Open questions at the time
    • Whether HR roles depend on catalytic activity for all targets unclear
    • Coordination of repair and mitotic functions of the same pool unresolved
  12. 2022 High

    Showed SIRT2 controls APP processing and TGF-β/SMAD signaling via deacetylation-coupled ubiquitination, linking it to neurodegeneration and fibrosis.

    Evidence Site-specific deacetylation with APP/PS1 behavioral rescue; SMAD2/3 deacetylation with SMURF2 ubiquitination assays and renal KO models

    PMID:35830807 PMID:37777567

    Open questions at the time
    • Whether deacetylation directly primes ubiquitination or acts indirectly not fully resolved
    • Neuronal vs systemic contributions to cognitive rescue not separated
  13. 2023 High

    Defined SIRT2 as a negative regulator of cGAS-STING innate immunity and a controller of cardiac aging via STAT3-CDKN2B and NRF2 axes.

    Evidence Site-specific G3BP1 deacetylation with cGAS activity assays and HSV-1 infection; proteomics and SIRT2-deficient iPSC-cardiomyocytes; cardiomyocyte Sirt2 x Nrf2 epistasis

    PMID:36786216 PMID:37728319 PMID:37783815 PMID:37870259

    Open questions at the time
    • Direct molecular nature of SIRT2-NRF2 regulation not specified
    • Balance between protective and detrimental cardiac roles context-dependent
  14. 2024 Medium

    Refined SIRT2's repair role through ATM/ATR-driven OGG1 recruitment and demonstrated that catalytic activity, not protein presence, underlies some phenotypes via PROTAC-vs-inhibitor comparison.

    Evidence ChIP and S46/S53 mutagenesis for OGG1-dependent BER; PROTAC degrader vs AGK2 inhibitor in IBD model targeting Arf6-E-cadherin endocytosis

    PMID:38554113 PMID:38648480

    Open questions at the time
    • Catalytic-independent scaffolding functions not systematically mapped
    • Distinct in vivo consequences of inhibition vs degradation not generalized across tissues

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SIRT2 selects among its very broad substrate set in a given cell type and subcellular compartment—and how its deacetylase, defatty-acylase, de-methacrylase, and scaffolding activities are coordinately deployed—remains unresolved.
  • No unifying model for compartment- and stimulus-specific substrate targeting
  • Relative physiological weight of catalytic vs non-catalytic functions undefined
  • Structural basis for multi-substrate recognition not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 15 GO:0098772 molecular function regulator activity 7 GO:0016787 hydrolase activity 4
Localization
GO:0005694 chromosome 3 GO:0005634 nucleus 2 GO:0005829 cytosol 2 GO:0005856 cytoskeleton 2 GO:0005576 extracellular region 1
Pathway
R-HSA-1430728 Metabolism 7 R-HSA-162582 Signal Transduction 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-1640170 Cell Cycle 3 R-HSA-73894 DNA Repair 3 R-HSA-168256 Immune System 2
Partners
BARD1BRCA1FOXO1G3BP1HIF1ALKB1NFATC2OGG1
Complex memberships
BRCA1-BARD1

Evidence

Reading pass · 52 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 SIRT2 deacetylates the APC/C coactivators CDH1 and CDC20, thereby regulating anaphase-promoting complex/cyclosome activity. Loss of SIRT2 increases levels of mitotic regulators Aurora-A and -B, leading to centrosome amplification and aneuploidy. Mouse knockout model, biochemical deacetylation assays, mitotic phenotype analysis Cancer cell High 22014574
2007 SIRT2 directly interacts with and deacetylates FOXO1, modulating insulin-stimulated phosphorylation and nuclear/cytosolic localization of FOXO1 to regulate adipocyte differentiation. Co-immunoprecipitation, overexpression and knockdown in 3T3-L1 cells, acetylation/phosphorylation assays Cell metabolism High 17681146
2014 SIRT2 deacetylates BubR1 at lysine 668, counteracting CBP-mediated acetylation, and thereby maintains BubR1 protein abundance. Decline in NAD+ with age reduces SIRT2 activity, lowering BubR1 levels. SIRT2 overexpression or NMN treatment increases BubR1 in vivo and extends lifespan in BubR1 hypomorphic mice. In vivo overexpression, NAD+ precursor (NMN) treatment, site-specific acetylation analysis, lifespan measurement in mouse models The EMBO journal High 24825348
2014 SIRT2 deacetylates phosphoglycerate mutase 2 (PGAM2) at lysine 100, an active-site residue, stimulating its enzymatic activity. Increased reactive oxygen species promote PGAM2 interaction with SIRT2, leading to deacetylation and increased NADPH production. In vitro deacetylation assay, site-directed mutagenesis (K100Q acetylation mimetic), Co-IP, ROS stimulation experiments Cancer research High 24786789
2014 SIRT2 directly interacts with HIF-1α and deacetylates it at Lys709, increasing HIF-1α binding to prolyl hydroxylase 2 (PHD2) and promoting HIF-1α hydroxylation, ubiquitination, and degradation under hypoxia. Co-IP, overexpression/knockdown, site-specific deacetylation assays, ubiquitination assays Oncogene High 24681946
2016 SIRT2 deacetylates PKM2 at lysine 305, promoting PKM2 tetramerization to its active enzymatic form and directing glycolytic metabolism. Loss of SIRT2 in cancer cells increases PKM2 acetylation, reducing tetramerization and reprogramming glycolysis. Shotgun mass spectrometry, site-directed mutagenesis, biochemical tetramerization assay, metabolic flux analysis, xenograft model Cancer research High 27197174
2016 SIRT2 deacetylates glucose-6-phosphate dehydrogenase (G6PD) at lysine 403, activating G6PD to promote NADPH production via the pentose phosphate pathway and support leukemia cell proliferation. Deacetylation assay, site-directed mutagenesis (K403), enzymatic activity measurement, knockdown/overexpression in AML cell lines Scientific reports High 27586085
2017 SIRT2 acts as a deacetylase for AMPA receptor (GluA1) subunits at their C-terminal lysine residues. Acetylation of AMPARs reduces internalization and degradation (increasing surface localization), competing with ubiquitination on the same residues. Sirt2 knockout increases AMPAR acetylation and protein accumulation, resulting in aberrant synaptic plasticity and impaired learning and memory. Sirt2 knockout mouse, acetylation/ubiquitination assays, surface receptor trafficking assay, electrophysiology, behavioral tests Cell reports High 28793258
2017 SIRT2 binds to and deacetylates LKB1 at lysine 48, promoting LKB1 phosphorylation and subsequent activation of LKB1-AMPK signaling, thereby protecting against cardiac hypertrophy. Co-IP, deacetylation assay, phosphorylation analysis, cardiac-specific transgenic and knockout mouse models, in vitro cardiomyocyte experiments Circulation High 28947430
2018 SIRT2 binds to and deacetylates NFATc2, preventing its nuclear localization and transcriptional activity. SIRT2 deficiency stabilizes NFATc2 and enhances nuclear translocation, promoting cardiac hypertrophy. NFAT inhibition rescues cardiac dysfunction in SIRT2-deficient mice. Co-IP, confocal microscopy, SIRT2 knockout mouse, NFAT luciferase reporter, pharmacological NFAT inhibition rescue The Journal of biological chemistry High 29440391
2018 SIRT2 deacetylates GKRP (glucokinase regulatory protein) at K126, promoting glucose-dependent dissociation of GKRP from glucokinase (GCK) and facilitating hepatic glucose uptake. Loss of SIRT2 impairs this dissociation and causes impaired glucose tolerance. In vivo overexpression/knockdown in mouse liver, deacetylation-mimicking and acetylation-mimicking GKRP mutants, glucose tolerance tests, Co-IP Nature communications High 29296001
2018 During Listeria monocytogenes infection, SIRT2 is dephosphorylated at serine 25 by a nuclear complex of phosphatases PPM1A and PPM1B, which is required for SIRT2 relocalization from cytoplasm to chromatin to deacetylate H3K18 and repress gene expression. Phosphoproteomics, site-directed mutagenesis (S25), subcellular fractionation, Co-IP, H3K18 deacetylation assay, infection model Cell reports High 29694890
2013 SIRT2 depletion in mouse oocytes causes spindle defects and chromosome disorganization. SIRT2 modulates acetylation of histone H4K16 and α-tubulin in oocytes, influencing microtubule dynamics and kinetochore function. siRNA knockdown in mouse oocytes, confocal microscopy, overexpression rescue, immunoblotting FASEB journal Medium 24334550
2017 Sirt2-dependent deacetylation of BubR1 at lysine 243 regulates meiotic apparatus in mouse oocytes. Acetylation-mimetic BubR1-K243Q recapitulates Sirt2-knockdown phenotypes (spindle/chromosome anomalies), and non-acetylatable BubR1-K243R partially rescues meiotic deficits caused by Sirt2 depletion. Knockdown, site-directed mutagenesis (K243Q, K243R), microinjection in mouse oocytes, confocal microscopy Aging cell High 29067790
2020 SIRT2 deacetylates IDH1 at lysine 224, promoting IDH1 enzymatic activity and α-ketoglutarate production. IDH1 hyperacetylation at K224 impairs activity and activates HIF1α-dependent SRC transcription, promoting colorectal cancer progression. Co-IP, site-specific mutagenesis, enzymatic activity assays, in vitro and in vivo invasion/migration assays EMBO reports High 32141187
2020 SIRT2 suppresses T cell metabolism by deacetylating key enzymes involved in glycolysis, TCA cycle, fatty acid oxidation, and glutaminolysis. Sirt2-deficient murine T cells exhibit increased glycolysis and oxidative phosphorylation with enhanced proliferation and effector functions. Sirt2 knockout mouse T cells, metabolomics, Seahorse metabolic flux assay, pharmacological inhibition of SIRT2, tumor infiltrating lymphocyte analysis Cell metabolism High 32768387
2021 Downregulation of SIRT2 increases acetylation of MEK1 at Lys175, activating ERK and subsequently DRP1 (pro-fission factor), and hyperacetylates AKT1 at Lys20, also activating DRP1. These two axes (SIRT2-MEK1-ERK-DRP1 and SIRT2-AKT1-DRP1) link SIRT2 to mitochondrial fission and metabolic reprogramming during somatic cell reprogramming. Acetylation assays, site-directed mutagenesis, Co-IP, mitochondrial morphology analysis, metabolic flux assays Cell reports High 34965411
2021 SIRT2 deacetylates C/EBPβ at lysines 102 and 211, reducing its ubiquitination and increasing C/EBPβ protein stability, which in turn enhances transcription of the target gene LCN2 and protects against alcoholic liver disease. Co-IP, site-specific deacetylation assays, ubiquitination assay, liver-specific knockout and transgenic mice, in vivo ethanol model Cell discovery High 34642310
2021 SIRT2 complexes with BRCA1-BARD1 and deacetylates conserved lysines in the BARD1 RING domain at the BRCA1 interface, promoting BRCA1-BARD1 heterodimerization, mutual stability, nuclear retention, localization to DNA damage sites, and efficient homologous recombination repair. Co-IP, deacetylation assay, site-directed mutagenesis, HR reporter assay, foci formation at DNA damage sites, nuclear fractionation Cell reports High 33789098
2021 Histone lysine methacrylation (Kmea) is a dynamic post-translational modification catalyzed by HAT1 as a methacryltransferase and reversed by SIRT2 as a de-methacrylase, as demonstrated by biochemical studies. In vitro enzymatic assay, mass spectrometry, antibody-based detection, biochemical characterization of writer (HAT1) and eraser (SIRT2) Cell discovery High 34961760
2022 SIRT2 deacetylates APP at lysines 132 and 134; suppression of SIRT2 enhances APP acetylation, promotes non-amyloidogenic processing of APP at the cell surface (increasing sAPPα), and ameliorates cognitive impairment in APP/PS1 transgenic mice. Genetic deletion and pharmacological inhibition of SIRT2, site-specific acetylation mapping, primary neuron protection assay, APP/PS1 mouse model behavioral testing Cell reports High 35830807
2022 SIRT2 deacetylates SMAD2 at lysine 451, promoting its ubiquitination (via SMURF2) and degradation, thereby suppressing TGF-β signaling. SIRT2 also deacetylates SMAD3 at lysines 341 and 378 in a TGF-β-dependent manner, reducing SMAD3 activation and renal fibrosis. Co-IP, deacetylation assay, site-directed mutagenesis, ubiquitination assay, renal tubule-specific KO and overexpression in vivo models Cell death & disease High 37777567
2023 SIRT2 deacetylates septin4 at K174, inhibiting the cleaved-PARP1-cleaved-caspase3 apoptosis pathway in renal podocytes and mitigating angiotensin II-induced hypertensive nephropathy. Immunoprecipitation, mass spectrometry, site-directed mutagenesis (K174Q/R), SIRT2 transgenic and knockout mice, proteomic/acetyl-proteomic analysis Circulation research High 36786216
2023 SIRT2 deacetylates G3BP1 at K257, K276, and K376, causing disassembly of the cGAS-G3BP1 complex, inhibiting cGAS DNA-binding ability and droplet formation, and thereby negatively regulating the cGAS-STING innate immune signaling pathway. Co-IP, site-directed mutagenesis, cGAS activity assays, AGK2 pharmacological inhibition, HSV-1 infection mouse model EMBO reports High 37870259
2023 SIRT2 deacetylates STAT3, and loss of SIRT2 leads to STAT3 hyperacetylation, which transcriptionally activates CDKN2B to trigger cardiomyocyte degeneration and senescence in aged primate hearts. Proteomic analysis of primate hearts, SIRT2-deficient human pluripotent stem cell-derived cardiomyocytes, lentiviral SIRT2 overexpression in aged mice, acetylation assays Nature aging High 37783815
2024 SIRT2 promotes base excision repair (BER) by interacting with OGG1 glycosylase (independent of SIRT2 catalytic activity) and promoting OGG1 recruitment to its own promoter under oxidative stress. ATM/ATR phosphorylate SIRT2 at S46 and S53 upon oxidative stress, enhancing the SIRT2-OGG1 interaction and OGG1 promoter activity. Co-IP, chromatin immunoprecipitation, site-directed mutagenesis (S46A, S53A), BER reporter assay, oxidative stress treatment Nucleic acids research High 38554113
2019 SIRT2 removes fatty acyl (myristoyl) groups from K-Ras4a lysine residues, regulating K-Ras4a transforming activity. SIRT2 also defatty-acylates RalB at K200, modulating RalB plasma membrane localization and recruitment of effectors Sec5 and Exo84 (exocyst complex), affecting cell migration. In vitro deacylation assay, fatty acylation detection, plasma membrane localization assay, Co-IP, cell migration assay ChemMedChem / ACS chemical biology High 30734528 31433161
2011 SIRT2 and HDAC6 act synergistically to deacetylate cortactin, promoting bladder cancer cell migration and invasion. Cortactin is a substrate of SIRT2. siRNA knockdown, HDAC6 inhibitor (tubacin), migration and invasion assays Oncology reports Medium 22089141
2014 SIRT2 interacts with MKP-1 (MAPK phosphatase-1); SIRT2 knockdown increases acetylation of MKP-1, suppresses p38 MAPK and JNK phosphorylation in LPS-treated renal tubular cells, and reduces CXCL2 and CCL2 expression. Co-IP, Western blot, siRNA knockdown, adenoviral overexpression, Sirt2 KO mouse model Journal of the American Society of Nephrology Medium 25349202
2013 SIRT2 deacetylates p65 (NF-κB) at K310, blocking p65 binding to the miR-21 promoter and repressing miR-21 transcription to suppress glioma cell growth. Overexpression, knockdown, chromatin immunoprecipitation, acetylation assay Biochemical and biophysical research communications Medium 24161395
2016 SIRT2 deacetylates Skp2 (an E3 ubiquitin ligase component), promoting Skp2 degradation and thereby increasing p27 levels to suppress non-small cell lung cancer cell growth. SIRT2 and Skp2 co-immunoprecipitate in NSCLC cells. Co-IP, deacetylation assay, SIRT2 overexpression/knockdown, proteasome inhibitor, lung cancer specimens Oncotarget Medium 26942878
2015 SIRT2 regulates microtubule stabilization in diabetic cardiomyopathy through deacetylation of α-tubulin. AGE/AGE receptor signaling impairs the SIRT2/acetylated α-tubulin axis. SIRT2 interacts with acetylated α-tubulin as demonstrated by Co-IP. Co-IP, Western blot, immunohistochemistry, STZ diabetic rat model, SIRT2 overexpression in cardiomyocytes European journal of pharmacology Medium 26209361
2020 SIRT2 deacetylates Hsp90α at K294, promoting dissociation of Hsp90 from glucocorticoid receptor (GR) and nuclear translocation of GR, which in turn represses inflammatory cytokine expression. Co-IP, mutation analysis (K294), GRE-reporter assay, overexpression/knockdown, LPS stimulation Journal of cellular and molecular medicine Medium 32515550
2018 SIRT2 directly interacts with Hsp70 and deacetylates it at K126. Vincristine disrupts Hsp70-SIRT2 binding, leading to K126 acetylation, altered Hsp70 chaperone function, sequestration of Bcl2 for autophagosome formation, and mitochondrial-mediated apoptosis. Co-IP, site-directed mutagenesis, chaperone activity assay, apoptosis assay, mitophagy analysis Biochemical pharmacology Medium 30352233
2018 SIRT2 directly interacts with HSP90 and regulates its acetylation and ubiquitination, targeting HSP90 for proteasomal degradation. This leads to suppression of LIM kinase (LIMK1)/cofilin pathway, inhibiting actin polymerization and cell migration. Co-IP, ubiquitination assay, actin polymerization assay, SIRT2 overexpression/knockdown Biochimica et biophysica acta. Molecular cell research Medium 29908203
2013 ERK1/2 interacts with SIRT2 (exogenous and endogenous) and increases SIRT2 protein levels, stability, and deacetylase activity. Co-IP, deacetylase activity assay, MEK inhibitor (U0126), constitutively active MEK overexpression Biochemical and biophysical research communications Medium 23806683
2014 c-Src kinase interacts with and phosphorylates SIRT2 at Tyr104, modulating SIRT2 protein levels (decreasing them) and regulating SIRT2 deacetylase activity. Co-IP, site-directed mutagenesis, Src inhibitor (SU6656), siRNA knockdown of c-Src, deacetylase activity assay Biochemical and biophysical research communications Medium 24996174
2021 SIRT2 depletion inhibits HR repair of DSBs, impairing RAD51 recruitment to DSB sites. SIRT2 depletion also decreases colocalization of γH2AX foci with RPA1, suggesting involvement in DSB end resection. I-SceI-based GFP HR reporter assay, siRNA depletion, RAD51 and RPA1 foci analysis Genes to cells Medium 33624391
2020 SUMOylation of SIRT2 at lysine 183 and lysine 340 is required for SIRT2 tumor-suppressor function in neuroblastoma. SUMOylated SIRT2 directly deacetylates MAPK/p38 to engage P38-mTORC2-AKT signaling. SUMOylation-deficient SIRT2 loses tumor-suppressive function. Site-directed mutagenesis, deacetylation assay on P38, siRNA, xenograft, pharmacological inhibitor (AK-7) resistance assay Neoplasia Medium 33316537
2021 SIRT2 deacetylates GKRP in pancreatic islet β-cells to regulate glucokinase activity and glycolytic flux, affecting glucose-stimulated insulin secretion. SIRT2 knockout increases GKRP stability and the GKRP-GCK interaction, while SIRT2 inhibition also promotes degradation of ALDOA. SIRT2 knockout rat, metabolomics, adenoviral overexpression, immunoprecipitation, insulin secretion assay Theranostics Medium 33754030
2022 SIRT2 interacts with Snail transcription factor and inhibits Snail degradation via its deacetylase activity, thereby maintaining Snail protein levels and promoting EMT and metastasis in osteosarcoma cells. Co-IP, deacetylase-inactive mutant, knockdown/overexpression, xenograft metastasis model Cell death & disease Medium 36344502
2022 SIRT2 mediates PGAM5 deacetylation to activate malic enzyme 1 (ME1) activity (via ME1 dephosphorylation), promoting lipid synthesis and liver cancer cell proliferation. Immunoprecipitation, mass spectrometry, enzymatic activity assay, overexpression/knockdown Acta biochimica et biophysica Sinica Medium 37580952
2023 SIRT2 deacetylates ACLY (ATP citrate lyase) in esophageal squamous cell carcinoma cells, promoting ACLY activity, lipid synthesis, and cancer cell proliferation and migration. Co-IP, AGK2 pharmacological inhibition, acetylation assay, overexpression rescue, xenograft model Journal of cellular and molecular medicine Medium 38426936
2023 SIRT2 is secreted extracellularly by macrophages following TLR4/TLR2 activation via TRAF6-mediated autophagy flux and autophagosome translocation. Extracellular SIRT2 (eSIRT2) deacetylates integrin β3 (ITGB3) at K416 in extracellular space, promoting cancer cell migration and metastasis. TLR activation, autophagy flux analysis, extracellular deacetylation assay, site-specific acetylation detection in lung cancer patient serum Advanced science Medium 36453571
2023 FHL1 enhances HOXA10 deacetylation by promoting HOXA10-SIRT2 binding, increasing HOXA10 protein stability and activity, thereby promoting blastocyst-epithelial adhesion via the β3 integrin/FAK pathway. Co-IP, SIRT2-specific inhibitor, deacetylation assay, overexpression/knockdown, in vivo embryo implantation assay Cell death discovery Medium 36418297
2024 SIRT2 deacetylates PFKP (phosphofructokinase-platelet isoform) at K394/K395, reducing glycolysis, PFKP-dependent Atg4B phosphorylation and LC3 activation, thereby suppressing LC3-associated phagocytosis (LAP) and pathogen clearance in ethanol-exposed macrophages. Co-IP, site-specific acetylation assay (K394), knockdown and pharmacological inhibition of SIRT2, LAP and phagocytosis assays, in vivo sepsis mouse model Frontiers in immunology Medium 36865524
2022 Sirt2 interacts with p27Kip1/FoxO1, p21Cip1/Cdk4, and Cdk5 pathways to promote oligodendrocyte differentiation. Under hypoxia, Sirt2 translocates to the nucleus in OPCs where it binds genomic targets. Hx disrupts these interactions. Co-IP, nuclear fractionation, ChIP, overexpression in OPCs, neonatal hypoxia mouse model Nature communications Medium 35970992
2023 SIRT2 modulates NRF2 cellular levels and activity; deletion of SIRT2 in cardiomyocytes increases NRF2-dependent antioxidant gene expression and protects against ischemia-reperfusion and pressure overload injury. Cardiac-specific deletion of Nrf2 reversed cardioprotection in Sirt2-knockout mice. Cardiomyocyte-specific Sirt2 knockout, Nrf2 double-knockout epistasis, NRF2 activity/protein level assays, cardiac functional measurements eLife Medium 37728319
2017 RNA-binding protein QKI directly binds Sirt2 mRNA via a quaking response element (QRE) in the 3'UTR, stabilizing Sirt2 transcripts and promoting SIRT2 protein expression during oligodendrocyte differentiation. RNA pulldown, QRE mutagenesis, mRNA half-life assay, QKI overexpression, qk viable mutant mouse The Journal of biological chemistry Medium 28188285
2024 FBXO31, an F-box protein, interacts with SIRT2 and promotes proteasome-dependent degradation of SIRT2, binding to the sirtuin-type domain of SIRT2. Co-IP, protein half-life assay, ubiquitination assay, domain mapping, cancer cell xenograft Cell death & disease Medium 38216561
2021 Wild-type GARS binds to SIRT2 via its catalytic domain and inhibits SIRT2 deacetylation activity, maintaining acetylated α-tubulin levels. CMT2D mutations in GARS disrupt this inhibition, leading to decreased α-tubulin acetylation. Genetic reduction of SIRT2 in a Drosophila model rescues GARS-induced axonal neuropathy. Co-IP, deacetylation activity assay, GARS mutation analysis, Drosophila genetic rescue model Aging cell Medium 34053152
2024 Sirt2 inhibition (by AGK2 or pharmacological inhibitor) improves gut epithelial barrier integrity in a mouse IBD model by inhibiting Arf6-mediated endocytosis of E-cadherin; PROTAC-mediated full degradation of Sirt2 did not recapitulate this protection, suggesting the effect is activity-specific rather than due to complete protein loss. PROTAC degrader, pharmacological inhibitors (TM, AGK2), E-cadherin endocytosis assay, Sirt2 knockout mouse, IBD mouse model Proceedings of the National Academy of Sciences of the United States of America Medium 38648480

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 SIRT2 maintains genome integrity and suppresses tumorigenesis through regulating APC/C activity. Cancer cell 444 22014574
2007 SIRT2 regulates adipocyte differentiation through FoxO1 acetylation/deacetylation. Cell metabolism 406 17681146
2013 SIRT1 and SIRT2: emerging targets in neurodegeneration. EMBO molecular medicine 336 23417962
2017 SIRT2 Acts as a Cardioprotective Deacetylase in Pathological Cardiac Hypertrophy. Circulation 276 28947430
2019 SIRT2: Controversy and multiple roles in disease and physiology. Ageing research reviews 220 31505260
2014 SIRT2 induces the checkpoint kinase BubR1 to increase lifespan. The EMBO journal 196 24825348
2021 SIRT1 and SIRT2 Activity Control in Neurodegenerative Diseases. Frontiers in pharmacology 136 33597872
2014 Oxidative stress activates SIRT2 to deacetylate and stimulate phosphoglycerate mutase. Cancer research 128 24786789
2016 SIRT2-Mediated Deacetylation and Tetramerization of Pyruvate Kinase Directs Glycolysis and Tumor Growth. Cancer research 118 27197174
2020 Sirt2 Inhibition Enhances Metabolic Fitness and Effector Functions of Tumor-Reactive T Cells. Cell metabolism 112 32768387
2014 SIRT2 regulates tumour hypoxia response by promoting HIF-1α hydroxylation. Oncogene 109 24681946
2013 Sirt2 functions in spindle organization and chromosome alignment in mouse oocyte meiosis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 107 24334550
2009 SIRT2-mediated protein deacetylation: An emerging key regulator in brain physiology and pathology. European journal of cell biology 106 20004495
2016 SIRT2 activates G6PD to enhance NADPH production and promote leukaemia cell proliferation. Scientific reports 101 27586085
2020 SIRT2-dependent IDH1 deacetylation inhibits colorectal cancer and liver metastases. EMBO reports 87 32141187
2020 The role of SIRT2 in cancer: A novel therapeutic target. International journal of cancer 86 32449165
2019 Review of the anti-inflammatory effect of SIRT1 and SIRT2 modulators on neurodegenerative diseases. European journal of pharmacology 82 31812544
2018 Sirt2 facilitates hepatic glucose uptake by deacetylating glucokinase regulatory protein. Nature communications 82 29296001
2018 SIRT2 deacetylase represses NFAT transcription factor to maintain cardiac homeostasis. The Journal of biological chemistry 82 29440391
2013 SIRT2: tumour suppressor or tumour promoter in operable breast cancer? European journal of cancer (Oxford, England : 1990) 82 24183459
2014 SIRT2 Regulates LPS-Induced Renal Tubular CXCL2 and CCL2 Expression. Journal of the American Society of Nephrology : JASN 80 25349202
2011 HDAC6 and SIRT2 promote bladder cancer cell migration and invasion by targeting cortactin. Oncology reports 74 22089141
2014 SIRT2 ameliorates lipopolysaccharide-induced inflammation in macrophages. Biochemical and biophysical research communications 70 25003320
2023 SIRT2 regulates extracellular vesicle-mediated liver-bone communication. Nature metabolism 69 37188819
2018 Infection Reveals a Modification of SIRT2 Critical for Chromatin Association. Cell reports 64 29694890
2023 SIRT2 counteracts primate cardiac aging via deacetylation of STAT3 that silences CDKN2B. Nature aging 61 37783815
2020 The Clinical Significance of SIRT2 in Malignancies: A Tumor Suppressor or an Oncogene? Frontiers in oncology 61 33014852
2022 Multiple Roles of SIRT2 in Regulating Physiological and Pathological Signal Transduction. Genetics research 57 36101744
2021 SIRT2 regulates mitochondrial dynamics and reprogramming via MEK1-ERK-DRP1 and AKT1-DRP1 axes. Cell reports 56 34965411
2020 SIRT2 Contributes to the Regulation of Intestinal Cell Proliferation and Differentiation. Cellular and molecular gastroenterology and hepatology 54 31954883
2022 Colchicine Ameliorates Dilated Cardiomyopathy Via SIRT2-Mediated Suppression of NLRP3 Inflammasome Activation. Journal of the American Heart Association 53 35766262
2017 Crucial Roles for SIRT2 and AMPA Receptor Acetylation in Synaptic Plasticity and Memory. Cell reports 51 28793258
2015 SIRT2 regulates microtubule stabilization in diabetic cardiomyopathy. European journal of pharmacology 51 26209361
2013 Sirt2 suppresses glioma cell growth through targeting NF-κB-miR-21 axis. Biochemical and biophysical research communications 49 24161395
2022 Inhibition of SIRT2 promotes APP acetylation and ameliorates cognitive impairment in APP/PS1 transgenic mice. Cell reports 47 35830807
2021 Histone lysine methacrylation is a dynamic post-translational modification regulated by HAT1 and SIRT2. Cell discovery 47 34961760
2019 A Small-Molecule SIRT2 Inhibitor That Promotes K-Ras4a Lysine Fatty-Acylation. ChemMedChem 46 30734528
2021 SIRT2-mediated deacetylation and deubiquitination of C/EBPβ prevents ethanol-induced liver injury. Cell discovery 45 34642310
2015 SIRT2 is involved in the modulation of depressive behaviors. Scientific reports 45 25672834
2016 HSPB1 Enhances SIRT2-Mediated G6PD Activation and Promotes Glioma Cell Proliferation. PloS one 44 27711253
2017 RNA-binding Protein Quaking Stabilizes Sirt2 mRNA during Oligodendroglial Differentiation. The Journal of biological chemistry 43 28188285
2023 Deacetylation of Septin4 by SIRT2 (Silent Mating Type Information Regulation 2 Homolog-2) Mitigates Damaging of Hypertensive Nephropathy. Circulation research 41 36786216
2020 Simultaneous Inhibition of SIRT2 Deacetylase and Defatty-Acylase Activities via a PROTAC Strategy. ACS medicinal chemistry letters 41 33214845
2017 Sirt2-BubR1 acetylation pathway mediates the effects of advanced maternal age on oocyte quality. Aging cell 40 29067790
2021 SIRT2 ablation inhibits glucose-stimulated insulin secretion through decreasing glycolytic flux. Theranostics 39 33754030
2018 Novel small molecule SIRT2 inhibitors induce cell death in leukemic cell lines. BMC cancer 39 30081901
2018 HBx-elevated SIRT2 promotes HBV replication and hepatocarcinogenesis. Biochemical and biophysical research communications 37 29366781
2016 SIRT2 inhibits non-small cell lung cancer cell growth through impairing Skp2-mediated p27 degradation. Oncotarget 36 26942878
2021 SIRT2 promotes BRCA1-BARD1 heterodimerization through deacetylation. Cell reports 33 33789098
2014 Mammalian SIRT2 inhibits keratin 19 expression and is a tumor suppressor in skin. Experimental dermatology 33 24438005
2014 SIRT1 and SIRT2 inhibition impairs pediatric soft tissue sarcoma growth. Cell death & disease 33 25341037
2021 The role of SIRT2 in vascular-related and heart-related diseases: A review. Journal of cellular and molecular medicine 31 34028177
2020 SIRT2 inhibits oxidative stress and inflammatory response in diabetic osteoarthritis. European review for medical and pharmacological sciences 31 32271403
2019 The SIRT2/cMYC Pathway Inhibits Peroxidation-Related Apoptosis In Cholangiocarcinoma Through Metabolic Reprogramming. Neoplasia (New York, N.Y.) 31 30933885
2019 SIRT2 and Lysine Fatty Acylation Regulate the Activity of RalB and Cell Migration. ACS chemical biology 31 31433161
2023 SIRT2 negatively regulates the cGAS-STING pathway by deacetylating G3BP1. EMBO reports 30 37870259
2023 Development of First-in-Class Dual Sirt2/HDAC6 Inhibitors as Molecular Tools for Dual Inhibition of Tubulin Deacetylation. Journal of medicinal chemistry 30 37902787
2024 NAD+ precursors promote the restoration of spermatogenesis in busulfan-treated mice through inhibiting Sirt2-regulated ferroptosis. Theranostics 29 38646657
2022 Sirt2 promotes white matter oligodendrogenesis during development and in models of neonatal hypoxia. Nature communications 29 35970992
2020 SIRT2 suppresses expression of inflammatory factors via Hsp90-glucocorticoid receptor signalling. Journal of cellular and molecular medicine 27 32515550
2024 FBXO31 is upregulated by METTL3 to promote pancreatic cancer progression via regulating SIRT2 ubiquitination and degradation. Cell death & disease 26 38216561
2023 SIRT2 alleviated renal fibrosis by deacetylating SMAD2 and SMAD3 in renal tubular epithelial cells. Cell death & disease 26 37777567
2018 Vincristine ablation of Sirt2 induces cell apoptosis and mitophagy via Hsp70 acetylation in MDA-MB-231 cells. Biochemical pharmacology 26 30352233
2023 SIRT2 inhibition protects against cardiac hypertrophy and ischemic injury. eLife 25 37728319
2019 Recent Progress on the Discovery of Sirt2 Inhibitors for the Treatment of Various Cancers. Current topics in medicinal chemistry 25 31074370
2024 SIRT2 as a potential new therapeutic target for Alzheimer's disease. Neural regeneration research 24 37488853
2018 SIRT2 reduces actin polymerization and cell migration through deacetylation and degradation of HSP90. Biochimica et biophysica acta. Molecular cell research 24 29908203
2021 Inhibition of Sirt2 Alleviates Fibroblasts Activation and Pulmonary Fibrosis via Smad2/3 Pathway. Frontiers in pharmacology 23 34925016
2014 Is SIRT2 required for necroptosis? Nature 23 24572428
2021 Pharmacological Advantage of SIRT2-Selective versus pan-SIRT1-3 Inhibitors. ACS chemical biology 22 34139124
2024 Nampt/SIRT2/LDHA pathway-mediated lactate production regulates follicular dysplasia in polycystic ovary syndrome. Free radical biology & medicine 21 39489197
2022 SIRT2 promotes the viability, invasion and metastasis of osteosarcoma cells by inhibiting the degradation of Snail. Cell death & disease 21 36344502
2020 Inhibiting Protein Kinase Activity of Pyruvate Kinase M2 by SIRT2 Deacetylase Attenuates Psoriasis. The Journal of investigative dermatology 20 32679047
2019 New SIRT2 inhibitors: Histidine-based bleomycin spin-off. Bioorganic & medicinal chemistry 20 30885568
2024 Sirt2 inhibition improves gut epithelial barrier integrity and protects mice from colitis. Proceedings of the National Academy of Sciences of the United States of America 19 38648480
2023 SIRT2-PFKP interaction dysregulates phagocytosis in macrophages with acute ethanol-exposure. Frontiers in immunology 19 36865524
2025 S-ketamine Alleviates Neuroinflammation and Attenuates Lipopolysaccharide-Induced Depression Via Targeting SIRT2. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 18 40171943
2021 Regulation of SIRT2 by Wnt/β-catenin signaling pathway in colorectal cancer cells. Biochimica et biophysica acta. Molecular cell research 18 33450304
2021 PHD Finger Protein 19 Promotes Cardiac Hypertrophy via Epigenetically Regulating SIRT2. Cardiovascular toxicology 18 33611744
2020 COXIV and SIRT2-mediated G6PD deacetylation modulate ROS homeostasis to extend pupal lifespan. The FEBS journal 18 33058529
2024 Trilobatin suppresses aging-induced cognitive impairment by targeting SIRT2: Involvement of remodeling gut microbiota to mediate the brain-gut axis. Phytomedicine : international journal of phytotherapy and phytopharmacology 17 38763011
2023 PGAM5 deacetylation mediated by SIRT2 facilitates lipid metabolism and liver cancer proliferation. Acta biochimica et biophysica Sinica 17 37580952
2013 ERK1/2 regulates SIRT2 deacetylase activity. Biochemical and biophysical research communications 17 23806683
2023 Knockout of Sirt2 alleviates traumatic brain injury in mice. Neural regeneration research 16 35900429
2023 Cooperative effects of SIRT1 and SIRT2 on APP acetylation. Aging cell 16 37602729
2022 Quantitative proteomic analysis of the lysine acetylome reveals diverse SIRT2 substrates. Scientific reports 16 35264593
2021 SIRT2 promotes murine melanoma progression through natural killer cell inhibition. Scientific reports 16 34155309
2021 Emerging role of SIRT2 in non-small cell lung cancer. Oncology letters 16 34429771
2020 SUMOylation is essential for Sirt2 tumor-suppressor function in neuroblastoma. Neoplasia (New York, N.Y.) 16 33316537
2014 Src regulates the activity of SIRT2. Biochemical and biophysical research communications 16 24996174
2022 SIRT2 Deficiency Exacerbates Hepatic Steatosis via a Putative Role of the ER Stress Pathway. International journal of molecular sciences 15 35743232
2022 Promotion of Lung Cancer Metastasis by SIRT2-Mediated Extracellular Protein Deacetylation. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 15 36453571
2021 SIRT2-knockdown rescues GARS-induced Charcot-Marie-Tooth neuropathy. Aging cell 15 34053152
2020 Correlation Between SIRT2 3'UTR Gene Polymorphism and the Susceptibility to Alzheimer's Disease. Journal of molecular neuroscience : MN 15 32124252
2020 SIRT2 inhibition activates hypoxia-inducible factor 1α signaling and mediates neuronal survival. Biochemical and biophysical research communications 15 32819605
2024 SIRT2 promotes base excision repair by transcriptionally activating OGG1 in an ATM/ATR-dependent manner. Nucleic acids research 14 38554113
2022 SIRT2 Affects Cell Proliferation and Apoptosis by Suppressing the Level of Autophagy in Renal Podocytes. Disease markers 14 35493297
2024 SIRT2-mediated deacetylation of ACLY promotes the progression of oesophageal squamous cell carcinoma. Journal of cellular and molecular medicine 13 38426936
2022 FHL1 mediates HOXA10 deacetylation via SIRT2 to enhance blastocyst-epithelial adhesion. Cell death discovery 13 36418297
2021 Human SIRT2 and SIRT3 deacetylases function in DNA homologous recombinational repair. Genes to cells : devoted to molecular & cellular mechanisms 13 33624391

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