Affinage

SIRT2

NAD-dependent protein deacetylase sirtuin-2 · UniProt Q8IXJ6

Length
389 aa
Mass
43.2 kDa
Annotated
2026-04-28
100 papers in source corpus 44 papers cited in narrative 44 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SIRT2 is an NAD⁺-dependent deacylase that broadly regulates cell division fidelity, intermediary metabolism, immune signaling, and tissue homeostasis by deacetylating a diverse array of cytoplasmic and nuclear substrates. It controls mitotic checkpoint integrity by deacetylating APC/C coactivators CDH1/CDC20 and the checkpoint kinase BubR1, preventing centrosome amplification and aneuploidy (PMID:22014574, PMID:24825348, PMID:29067790); it tunes metabolic flux by activating G6PD, PGAM2, IDH1, GKRP, and PEPCK1, and restrains T cell metabolism through broad deacetylation of glycolytic and TCA cycle enzymes (PMID:27586085, PMID:24786789, PMID:32768387, PMID:29296001). SIRT2 also suppresses inflammatory and fibrotic signaling—deacetylating NF-κB p65, disassembling the cGAS–G3BP1 innate-sensing complex, and destabilizing SMAD2/3—while protecting the heart via LKB1-AMPK activation and NRF2 modulation (PMID:25072851, PMID:37870259, PMID:37777567, PMID:28947430, PMID:37728319). Beyond canonical deacetylation, SIRT2 removes histone lysine benzoylation and K-Ras4a fatty acyl groups, and its own activity is regulated by ERK1/2-mediated stabilization, c-Src phosphorylation at Tyr104, PPM1A/B-dependent S25 dephosphorylation governing chromatin access, and SUMOylation at K183/K340 that controls substrate selectivity (PMID:30154464, PMID:30734528, PMID:29694890, PMID:33316537).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2011 High

    Establishing SIRT2 as a mitotic regulator: it was unknown how SIRT2 influenced cell division fidelity; deacetylation of APC/C coactivators CDH1 and CDC20 and the resulting control of Aurora-A/B levels and centrosome number provided a direct mechanism linking SIRT2 loss to aneuploidy.

    Evidence SIRT2 knockout mouse with Co-IP and deacetylation assays showing centrosome amplification

    PMID:22014574

    Open questions at the time
    • Whether CDH1/CDC20 acetylation changes their APC/C substrate specificity was not resolved
    • Relationship between SIRT2-dependent APC/C regulation and tumorigenesis in specific tissues unclear
  2. 2012 High

    Revealing SIRT2 as a chromatin-level transcriptional repressor: direct promoter binding and H4K16 deacetylation at the NEDD4 locus showed SIRT2 could stabilize Myc oncoproteins through an indirect transcriptional mechanism, not only through cytoplasmic deacetylation.

    Evidence ChIP confirming SIRT2 binding to NEDD4 promoter, gene array, SIRT2 inhibitor treatment in cancer cells

    PMID:23175188

    Open questions at the time
    • Genome-wide scope of SIRT2 H4K16 deacetylation targets unknown
    • Relative contribution of nuclear vs. cytoplasmic SIRT2 pools was not quantified
  3. 2014 High

    Defining SIRT2 as a metabolic enzyme activator and aging-linked checkpoint regulator: deacetylation of PGAM2-K100 and BubR1-K668 established two mechanistic axes—metabolic enzyme control under oxidative stress and age-dependent mitotic checkpoint maintenance through NAD⁺ availability.

    Evidence In vitro deacetylation with active-site mutagenesis for PGAM2; in vivo NMN rescue and site-specific mutagenesis for BubR1; mouse lifespan analysis

    PMID:24786789 PMID:24825348

    Open questions at the time
    • Whether NAD⁺ decline preferentially affects SIRT2 vs. other sirtuins was not determined
    • Structural basis for SIRT2 recognition of PGAM2 active site lysine not resolved
  4. 2014 Medium

    Connecting SIRT2 to inflammatory signaling: direct deacetylation of NF-κB p65 established SIRT2 as an anti-inflammatory brake in macrophages, and interaction with MKP-1 revealed a parallel mechanism regulating MAPK-dependent chemokine expression.

    Evidence SIRT2 KO mouse macrophage polarization and DSS colitis model; Co-IP with MKP-1 and siRNA in renal tubular cells

    PMID:25072851 PMID:25349202

    Open questions at the time
    • Whether p65 deacetylation and MKP-1 regulation are coordinated or independent was not tested
    • Specific p65 lysine residue targeted by SIRT2 was not mapped in these studies
  5. 2016 High

    Expanding the metabolic substrate repertoire: SIRT2-mediated deacetylation of G6PD-K403 activates the pentose phosphate pathway for NADPH production, while deacetylation of Skp2 promotes its degradation to stabilize p27, revealing both metabolic and cell-cycle-inhibitory tumor-suppressive functions.

    Evidence Site-specific mutagenesis with NADPH measurement for G6PD; Co-IP and proteasome inhibitor experiments for Skp2

    PMID:26942878 PMID:27586085

    Open questions at the time
    • Whether SIRT2's effect on G6PD vs. glycolytic enzymes dominates in specific tumor types was unclear
    • HSPB1-mediated enhancement of the SIRT2-G6PD interaction awaits independent confirmation
  6. 2017 High

    Establishing SIRT2 in cardiac and hepatic physiology: deacetylation of LKB1-K48 activates AMPK to protect against cardiac hypertrophy, while deacetylation of GKRP-K126 regulates glucokinase compartmentalization in hepatocytes, and PEPCK1 stability control links SIRT2 to gluconeogenesis.

    Evidence Cardiac-specific transgenic/KO mice with Ang II model for LKB1; site-specific mutagenesis in hepatocytes and obese diabetic mice for GKRP; SIRT2 siRNA with glucose output assay for PEPCK1

    PMID:28127057 PMID:28947430 PMID:29296001

    Open questions at the time
    • Whether cardiac LKB1-AMPK axis is the sole or dominant SIRT2 cardioprotective mechanism was unresolved
    • Direct in vitro reconstitution of PEPCK1 deacetylation by SIRT2 was not shown
  7. 2018 High

    Demonstrating non-canonical catalytic activities and regulated nuclear entry: SIRT2 removes histone lysine benzoylation marks, broadening its enzymatic repertoire beyond deacetylation; separately, PPM1A/B-mediated S25 dephosphorylation during Listeria infection was shown to be the switch enabling SIRT2 chromatin association and H3K18 deacetylation.

    Evidence In vitro de-benzoylation assay with ChIP-seq/RNA-seq; MS-based PTM mapping with S25 mutagenesis and nuclear fractionation during infection

    PMID:29694890 PMID:30154464

    Open questions at the time
    • Physiological contexts beyond infection where S25 dephosphorylation occurs are unknown
    • Full spectrum of non-acetyl acyl modifications removed by SIRT2 in vivo not catalogued
  8. 2019 Medium

    Revealing SIRT2 as a protein defatty-acylase: removal of long-chain fatty acyl groups from K-Ras4a showed SIRT2 regulates Ras membrane association through a catalytic activity mechanistically distinct from deacetylation.

    Evidence In vitro defatty-acylation assay with cell-based K-Ras4a fatty acylation measurement and JH-T4 inhibitor

    PMID:30734528

    Open questions at the time
    • Functional consequence of altered K-Ras4a fatty acylation on Ras signaling was not fully tested
    • Selectivity of SIRT2 defatty-acylase activity toward other Ras family members is unknown
  9. 2020 High

    Positioning SIRT2 as a global metabolic checkpoint in T cells: Sirt2 KO T cells showed hyperacetylation of glycolytic, TCA, FAO, and glutaminolysis enzymes with enhanced metabolic flux, establishing SIRT2 as a broad suppressor of T cell effector metabolism.

    Evidence Sirt2 KO mouse T cells with Seahorse metabolic flux and quantitative acetyl-proteomics

    PMID:32768387

    Open questions at the time
    • Which individual metabolic enzyme deacetylation events are rate-limiting for T cell function is unresolved
    • Whether SIRT2 restraint on T cell metabolism contributes to immune evasion in tumors was not tested
  10. 2021 High

    Broadening signaling and tissue-protective substrates: deacetylation of MEK1-K175 and AKT1-K20 controls mitochondrial fission during reprogramming; deacetylation of C/EBPβ stabilizes the transcription factor to prevent alcoholic liver disease; and SIRT2 promotes Th17 via p70S6K deacetylation while restraining IL-2 via histone/c-Jun deacetylation.

    Evidence Site-specific mutagenesis for MEK1/AKT1; liver-specific KO/TG mice for C/EBPβ; Co-IP and T cell differentiation assays for p70S6K

    PMID:34642310 PMID:34965411 PMID:35523941

    Open questions at the time
    • How SIRT2 simultaneously promotes Th17 and suppresses other T cell programs mechanistically remains unclear
    • Whether C/EBPβ stabilization is the primary hepatoprotective mechanism of SIRT2 vs. metabolic enzyme regulation
  11. 2022 Medium

    Identifying upstream regulation and global substrate consensus: SIRT2 SUMOylation at K183/K340 is required for p38 MAPK deacetylation and tumor suppression; quantitative acetyl-proteomics revealed ~610 substrates enriched in carbon metabolism with a KxxxxK(ac) consensus motif; FBXO31/SCF promotes SIRT2 proteasomal degradation.

    Evidence K183/340 mutagenesis with deacetylation assays in neuroblastoma; label-free acetyl-proteomics in SIRT2-KD/OE HCT116 cells; Co-IP/ubiquitination assays for FBXO31

    PMID:33316537 PMID:35264593 PMID:38216561

    Open questions at the time
    • Whether SUMOylation dynamically switches SIRT2 substrate selectivity in vivo is untested
    • The KxxxxK(ac) motif prediction was not validated with in vitro kinetic assays on individual sites
  12. 2022 High

    Linking SIRT2 to Alzheimer's disease pathology: SIRT2 deacetylates APP at K132/K134, and SIRT2 inhibition or KO shifts APP processing toward the non-amyloidogenic pathway, reducing Aβ42 toxicity in APP/PS1 mice.

    Evidence Site-specific mutagenesis, pharmacological inhibition, SIRT2 KO in APP/PS1 Alzheimer's model, primary neuron Aβ challenge

    PMID:35830807

    Open questions at the time
    • Whether SIRT1 competitive inhibition of SIRT2-APP interaction operates in vivo under disease conditions is not established
    • Long-term cognitive outcomes of SIRT2 inhibition were not assessed
  13. 2023 High

    Expanding into innate immunity, cardiac aging, fibrosis, and extracellular function: SIRT2 deacetylation of G3BP1 disassembles the cGAS complex to suppress type I IFN; STAT3 deacetylation prevents cardiomyocyte senescence; SMAD2/3 deacetylation inhibits TGF-β fibrosis; septin4-K174 deacetylation protects podocytes; NRF2 modulation mediates cardiac stress responses; and macrophage-secreted SIRT2 deacetylates integrin β3 extracellularly.

    Evidence Multiple KO/transgenic models with site-specific mutagenesis for G3BP1, STAT3, SMAD2/3, septin4; cardiac-specific KO with NRF2 epistasis; subcellular fractionation and migration assay for extracellular SIRT2

    PMID:36453571 PMID:36786216 PMID:37728319 PMID:37777567 PMID:37783815 PMID:37870259

    Open questions at the time
    • Mechanism by which SIRT2 modulates NRF2 levels (direct deacetylation vs. indirect) is not identified
    • Physiological relevance and regulation of extracellular SIRT2 secretion beyond macrophage TLR activation unknown
    • Whether septin4 and SMAD2/3 pathways converge in chronic kidney disease is untested
  14. 2024 High

    Demonstrating substrate-selective pharmacology: SIRT2 inhibition (but not complete degradation) protects gut epithelium by blocking Arf6-mediated E-cadherin endocytosis, revealing that partial enzymatic inhibition and full protein loss produce different outcomes.

    Evidence Pharmacological inhibitors vs. PROTAC degrader vs. Sirt2 KO in DSS colitis model with E-cadherin endocytosis assay

    PMID:38648480

    Open questions at the time
    • Identity of the specific SIRT2 substrate whose partial deacetylation maintains E-cadherin at the surface is unknown
    • Whether SIRT2 scaffolding functions independent of catalytic activity exist broadly is untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include: the structural basis for SIRT2's broad yet selective substrate recognition across deacetylation, de-benzoylation, and defatty-acylation activities; how dynamic post-translational modifications (SUMOylation, S25 phosphorylation, Tyr104 phosphorylation) integrate to determine substrate selectivity in specific tissues and stress states; and whether pharmacological strategies can selectively target individual SIRT2 substrate axes for therapeutic benefit.
  • No co-crystal structure of SIRT2 with a protein substrate
  • No systematic comparison of deacetylase vs. defatty-acylase vs. de-benzoylase activities on shared substrates
  • Tissue-specific SIRT2 interactome not comprehensively mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 15 GO:0042393 histone binding 3 GO:0016787 hydrolase activity 2 GO:0140110 transcription regulator activity 2
Localization
GO:0005829 cytosol 6 GO:0005634 nucleus 3 GO:0005694 chromosome 2 GO:0005576 extracellular region 1
Pathway
R-HSA-1430728 Metabolism 7 R-HSA-162582 Signal Transduction 5 R-HSA-1640170 Cell Cycle 5 R-HSA-168256 Immune System 4 R-HSA-5357801 Programmed Cell Death 2 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-8953854 Metabolism of RNA 1
Partners
BUBR1CDC20CDH1G3BP1G6PDGKRPLKB1NRF2

Evidence

Reading pass · 44 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 SIRT2 deacetylates the APC/C coactivators CDH1 and CDC20, regulating anaphase-promoting complex/cyclosome activity. SIRT2 deficiency causes increased levels of mitotic regulators Aurora-A and -B, leading to centrosome amplification and aneuploidy. Mouse knockout, co-immunoprecipitation, deacetylation assays, mitotic phenotype analysis Cancer cell High 22014574
2014 SIRT2 maintains BubR1 (mitotic checkpoint kinase) in a deacetylated state at lysine-668, counteracting acetylation by CBP. Declining NAD+ with age reduces SIRT2 activity, leading to BubR1 loss; NMN or SIRT2 overexpression restores BubR1 abundance in vivo. In vivo overexpression, NAD+ precursor treatment, site-specific acetylation mutagenesis, mouse lifespan analysis The EMBO journal High 24825348
2014 SIRT2 deacetylates phosphoglycerate mutase 2 (PGAM2) at the active site residue lysine-100, stimulating its enzymatic activity. Increased reactive oxygen species promote PGAM2 deacetylation by enhancing its interaction with SIRT2, linking oxidative stress to NADPH homeostasis. In vitro deacetylation assay, Co-IP, acetylation-mimetic mutagenesis (K100Q), cell proliferation and tumor growth assays Cancer research High 24786789
2016 SIRT2 deacetylates glucose-6-phosphate dehydrogenase (G6PD) at lysine-403, activating G6PD to promote NADPH production and support leukemia cell proliferation via the pentose phosphate pathway. Site-specific mutagenesis, enzymatic activity assay, knockdown/overexpression, NADPH measurement Scientific reports High 27586085
2016 HSPB1 enhances the binding between G6PD and SIRT2, facilitating SIRT2-mediated deacetylation and activation of G6PD in response to oxidative stress or DNA damage, thereby sustaining cellular NADPH and pentose production. Co-IP, overexpression, G6PD activity assays in glioma cells PloS one Medium 27711253
2016 SIRT2 deacetylates Skp2 (an E3 ubiquitin ligase component), promoting Skp2 degradation and thereby preventing Skp2-mediated p27 ubiquitination and degradation, which suppresses non-small cell lung cancer cell growth. Co-IP, overexpression/knockdown, proteasome inhibitor experiments, patient tissue analysis Oncotarget Medium 26942878
2017 SIRT2 deacetylates LKB1 at lysine-48, promoting LKB1 phosphorylation and subsequent activation of LKB1-AMPK signaling, thereby protecting against pathological cardiac hypertrophy. Co-IP, site-specific deacetylation assay, SIRT2 KO and cardiac-specific transgenic mice, Ang II cardiac hypertrophy model Circulation High 28947430
2017 SIRT2 deacetylates glucokinase regulatory protein (GKRP) at K126, promoting glucose-dependent dissociation of GKRP from glucokinase and facilitating hepatic glucose uptake. Co-IP, site-specific mutagenesis (K126R/Q), hepatocyte assays, in vivo Sirt2 overexpression/knockdown in obese diabetic mice Nature communications High 29296001
2017 SIRT2 inhibition by sirtinol causes PEPCK1 hyperacetylation and proteasomal degradation, thereby reducing gluconeogenesis; sirtinol had no effect in SIRT2-knockdown cells, demonstrating PEPCK1 as a primary SIRT2 substrate. Immunoblotting, SIRT2 siRNA knockdown, glucose output assay, in vivo mouse studies Scientific reports Medium 28127057
2018 SIRT2 removes lysine benzoylation (Kbz) marks from histones both in vitro and in vivo, revealing a non-canonical deacylase activity of SIRT2 beyond acetylation. In vitro deacylation assay, cell-based Kbz measurement, ChIP-seq, RNA-seq Nature communications High 30154464
2018 Listeria monocytogenes infection induces dephosphorylation of SIRT2 at serine-25 by nuclear phosphatases PPM1A and PPM1B, which is essential for SIRT2 chromatin association and H3K18 deacetylation-mediated gene repression during infection. Mass spectrometry mapping of PTMs, site-specific mutagenesis, nuclear fractionation, Co-IP with phosphatases, ChIP Cell reports High 29694890
2018 SIRT2 interacts with and deacetylates Hsp90α at K294, leading to dissociation of Hsp90 from glucocorticoid receptor (GR) and nuclear translocation of GR, which suppresses inflammatory cytokine expression. Co-IP, site-specific mutagenesis, GRE-reporter assay, SIRT2 overexpression/knockdown Journal of cellular and molecular medicine Medium 32515550
2018 SIRT2 physically binds Hsp70 and maintains it in a deacetylated state; vincristine disrupts this interaction, causing Hsp70 acetylation at K126, which alters its chaperone activity and promotes mitophagy and apoptosis. Co-IP, site-specific mutagenesis at K126, cell death and autophagy assays Biochemical pharmacology Medium 30352233
2012 SIRT2 binds to the NEDD4 gene core promoter and deacetylates histone H4 lysine-16 to repress NEDD4 expression; NEDD4 ubiquitinates Myc oncoproteins, so SIRT2-mediated NEDD4 repression stabilizes N-Myc and c-Myc, promoting cancer cell proliferation. ChIP, gene array, promoter binding assay, SIRT2 inhibitor treatment, Myc protein stability assay Cell death and differentiation High 23175188
2013 Sirt2 depletion in mouse oocytes causes spindle defects and chromosome disorganization; Sirt2 modulates acetylation of histone H4K16 and α-tubulin in oocytes, affecting microtubule dynamics and kinetochore function during meiosis. Confocal microscopy, knockdown/overexpression, immunoblotting for acetylation marks in oocytes FASEB journal Medium 24334550
2017 Sirt2-dependent deacetylation of BubR1 at lysine-243 regulates spindle assembly checkpoint function in oocyte meiosis; acetylation-mimetic BubR1-K243Q phenocopies Sirt2 depletion, and non-acetylatable BubR1-K243R rescues meiotic defects in Sirt2-depleted oocytes from aged mice. Site-specific mutagenesis, oocyte microinjection, spindle/chromosome phenotype analysis Aging cell High 29067790
2019 SIRT2 removes long-chain fatty acyl groups (demyristoylation) from K-Ras4a, a non-deacetylation activity. Small-molecule inhibitor JH-T4 blocks this activity and increases K-Ras4a lysine fatty acylation in cells. In vitro defatty-acylation assay, cell-based K-Ras4a fatty acylation measurement ChemMedChem Medium 30734528
2020 SIRT2 deacetylates IDH1 at lysine-224, promoting IDH1 enzymatic activity and α-KG production; SIRT2 was identified as a major IDH1 deacetylase and its overexpression inhibits colorectal cancer cell migration and invasion. Co-IP, site-specific mutagenesis, enzymatic activity assay, in vitro and in vivo invasion assays EMBO reports High 32141187
2020 Sirt2 suppresses T cell metabolism by targeting key glycolytic, TCA cycle, fatty acid oxidation, and glutaminolysis enzymes through deacetylation; Sirt2-deficient T cells show increased glycolysis and oxidative phosphorylation with enhanced effector function. Sirt2 KO mouse T cells, metabolic flux analysis (Seahorse), quantitative proteomics of metabolic enzyme acetylation Cell metabolism High 32768387
2021 SIRT2 deacetylates MEK1 at Lys175 and AKT1 at Lys20; downregulation of SIRT2 leads to hyperacetylation of these kinases, activating ERK and DRP1-mediated mitochondrial fission, and promoting metabolic reprogramming during somatic cell reprogramming. Site-specific mutagenesis, co-immunoprecipitation, phosphorylation and acetylation western blotting, mitochondrial dynamics imaging Cell reports High 34965411
2021 SIRT2 deacetylates p70S6K (activating mTORC1/HIF-1α/RORγt pathway to promote Th17 differentiation) and deacetylates c-Jun and histones at the IL-2 gene locus (reducing IL-2 production) in CD4+ T cells. Co-IP, site-specific mutagenesis, pharmacological inhibition (AK-7), T cell differentiation assays in vitro and in vivo Cellular & molecular immunology Medium 35523941
2021 SIRT2 mediates deacetylation-deubiquitination switch of C/EBPβ at lysines 102 and 211; SIRT2-mediated deacetylation decreases C/EBPβ ubiquitination, stabilizing the protein and increasing transcription of LCN2, thereby preventing alcoholic liver disease. Co-IP, site-specific mutagenesis, protein half-life assay, liver-specific KO and transgenic mice, ubiquitination assay Cell discovery High 34642310
2022 SIRT2 deacetylates APP at lysines K132 and K134, and inhibition of SIRT2 promotes non-amyloidogenic APP processing at the cell surface, increasing sAPPα and reducing Aβ42 toxicity in Alzheimer's disease mouse models. Site-specific mutagenesis, pharmacological inhibition, SIRT2 KO mouse (APP/PS1 model), primary neuron Aβ challenge assay Cell reports High 35830807
2023 SIRT1 blocks SIRT2-mediated APP deacetylation by inhibiting SIRT2 binding to APP; loss of SIRT1 reduces APP recycling to the cell surface and promotes amyloidogenic processing. Co-IP, overexpression experiments, APP trafficking assays, HT22 cells with Aβ challenge Aging cell Medium 37602729
2023 SIRT2 deacetylates STAT3, and loss of SIRT2 in human cardiomyocytes leads to STAT3 hyperacetylation, which transcriptionally activates CDKN2B, triggering cardiomyocyte degeneration and senescence. Co-IP, acetylation assays, SIRT2 KO human iPSC-derived cardiomyocytes, gene expression analysis, in vivo SIRT2 lentiviral injection in aged mice Nature aging High 37783815
2023 SIRT2 deacetylates septin4 at K174; hyperacetylation of septin4-K174 activates the cleaved-PARP1-cleaved-caspase3 apoptosis pathway in podocytes, exacerbating hypertensive nephropathy. SIRT2 interacts with the septin4 GTPase domain. Immunoprecipitation, mass spectrometry, site-specific mutagenesis (K174R/Q transgenic mice), proteomic/acetyl-proteomic analysis, SIRT2 KO and TG mice Circulation research High 36786216
2023 SIRT2 negatively regulates the cGAS-STING pathway by deacetylating G3BP1 at K257, K276, and K376, which disassembles the cGAS-G3BP1 complex required for cGAS activation, thereby inhibiting type I interferon production during HSV-1 infection. Co-IP, site-specific mutagenesis, in vitro deacetylation assay, SIRT2 KO cells and mice, IFN expression measurement EMBO reports High 37870259
2023 SIRT2 deacetylates SMAD2 at K451 (promoting ubiquitination and degradation by SMURF2) and SMAD3 at K341 and K378 (reducing activation in TGF-β-dependent manner), thereby inhibiting TGF-β fibrotic signaling in renal tubular epithelial cells. Co-IP, site-specific mutagenesis, ubiquitination assay, renal tubule-specific KO and overexpression mice Cell death & disease High 37777567
2023 SIRT2 is secreted by macrophages following TLR2/4 activation via TRAF6-mediated autophagy flux into the extracellular space; extracellular SIRT2 deacetylates integrin β3 at K416, promoting cancer cell attachment and migration. Subcellular fractionation, autophagosome tracking, in vitro deacetylation assay, cell migration assay, patient serum measurements Advanced science Medium 36453571
2023 SIRT2 deacetylates PGAM5, which activates malic enzyme 1 (ME1) by promoting its dephosphorylation, leading to lipid accumulation and proliferation of liver cancer cells (SIRT2-PGAM5-ME1 axis). Immunoprecipitation, mass spectrometry, ME1 activity assay, knockdown experiments Acta biochimica et biophysica Sinica Medium 37580952
2023 SIRT2 modulates NRF2 cellular levels and activity, resulting in reduced antioxidant protein expression; cardiac-specific Sirt2 deletion improves cardiac function after ischemia-reperfusion and pressure overload, and Nrf2 deletion reverses this protection. Cardiac-specific Sirt2 KO mice, I/R and pressure overload models, epistasis with Nrf2 KO, pharmacological SIRT2 inhibitor eLife High 37728319
2023 FBXO31 (SCF complex F-box protein) binds to the sirtuin-type domain of SIRT2 and promotes proteasome-dependent degradation of SIRT2; METTL3 induces m6A modification of FBXO31 mRNA to upregulate FBXO31, thereby reducing SIRT2 in pancreatic cancer. Co-IP, protein half-life assay, ubiquitination assay, METTL3 m6A modification analysis Cell death & disease Medium 38216561
2014 SIRT2 directly deacetylates the p65 subunit of NF-κB, inhibiting NF-κB activity; SIRT2 deficiency increases NF-κB acetylation and promotes pro-inflammatory macrophage polarization. SIRT2 KO mouse, macrophage polarization assays, DSS colitis model PloS one Medium 25072851
2014 SIRT2 interacts with MKP-1 (MAPK phosphatase-1); SIRT2 knockdown increases MKP-1 acetylation and suppresses p38 MAPK and JNK phosphorylation in LPS-treated renal tubular cells, regulating CXCL2 and CCL2 expression. Co-IP, siRNA knockdown, adenovirus overexpression, phosphorylation western blotting Journal of the American Society of Nephrology Medium 25349202
2013 ERK1/2 interacts with SIRT2, increases SIRT2 protein stability, and upregulates its deacetylase activity; constitutively active MEK increases SIRT2 levels while MEK inhibitor U0126 suppresses them. Co-IP, MEK overexpression and inhibition, SIRT2 deacetylase activity assay Biochemical and biophysical research communications Medium 23806683
2014 c-Src tyrosine kinase interacts with SIRT2 and phosphorylates it at Tyr104, reducing SIRT2 protein levels and modulating its deacetylase activity. Co-IP, Src inhibitor (SU6656), siRNA knockdown, SIRT2 deacetylase activity assay Biochemical and biophysical research communications Medium 24996174
2022 SUMOylation of Sirt2 at lysines 183 and 340 is essential for its tumor-suppressor function; SUMOylation enables Sirt2 to deacetylate MAPK/p38 and regulate P38-mTORC2-AKT signaling. SUMOylation-deficient Sirt2 loses its ability to suppress neuroblastoma tumor processes. Site-specific mutagenesis (K183/340), Co-IP, deacetylation assay on p38, cell tumor assays, Sirt2 inhibitor AK-7 Neoplasia Medium 33316537
2022 Quantitative proteomics identified 610 proteins with >1.5-fold increased acetylation upon SIRT2 knockdown; SIRT2 substrates cluster in carbon metabolism, glycolysis, spliceosome, RNA transport, DNA damage response, and cell cycle pathways with a consensus KxxxxK(ac) motif. Label-free quantitative proteomics with acetyl-peptide enrichment from SIRT2-KD and OE HCT116 cells Scientific reports Medium 35264593
2020 SIRT2 interacts with and stabilizes Snail (EMT transcription factor) by inhibiting its degradation via deacetylase activity, thereby promoting osteosarcoma cell migration and invasion. Co-IP, deacetylase activity-dependent rescue experiment, knockdown/overexpression, xenograft mouse model Cell death & disease Medium 36344502
2024 Sirt2 inhibition protects gut epithelial barrier integrity by inhibiting Arf6-mediated endocytosis of E-cadherin; a PROTAC degrader of Sirt2 (like genetic KO) did not protect, indicating the protective effect involves partial inhibition of a specific Sirt2 substrate activity. Pharmacological inhibition (TM, AGK2), PROTAC degrader, Sirt2 KO mice, DSS colitis model, E-cadherin endocytosis assay Proceedings of the National Academy of Sciences of the United States of America High 38648480
2011 SIRT2 expression in oligodendrocytes is regulated post-translationally through the QKI-PLP pathway; SIRT2 protein in myelin is dependent on PLP (proteolipid protein) expression, and its cellular function in regulating process complexity is independent of PLP in non-myelinating oligodendrocytes. Quaking viable (qkv) mutant mouse analysis, PLP-ISEdel mutant mouse, Western blot, rescue by QKI6 overexpression Glia Medium 21948283
2020 Cortactin deacetylation by SIRT2 (and HDAC6) regulates neuronal migration and dendrite morphogenesis; acetyl-mimetic cortactin 9KQ impairs both radial migration and apical dendrite formation during cortex development, and SIRT2 can rescue HDAC6 knockdown dendritic defects. In utero electroporation, shRNA knockdown, cortactin acetylation mutagenesis (9KR/9KQ), confocal imaging of migration and dendrite phenotypes Molecular brain Medium 32711564
2022 Sirt2 interacts with p27Kip1/FoxO1, p21Cip1/Cdk4, and Cdk5 pathways to promote oligodendrocyte differentiation; hypoxia reduces Sirt2 expression in mature oligodendrocytes and induces nuclear translocation of Sirt2 in OPCs where it binds genomic targets. Sirt2 KO mouse, Sirt2 OPC overexpression, neonatal hypoxia model, nuclear fractionation, ChIP Nature communications Medium 35970992
2016 SIRT2 inhibition promotes degradation of c-MYC by suppressing ERK phosphorylation (which stabilizes c-MYC); the SIRT2/ERK/c-MYC axis is required for hepatic stellate cell activation and liver fibrosis. SIRT2 shRNA/inhibitor, ERK phosphorylation analysis, c-MYC stability assay, CCl4/TAA mouse fibrosis model, SIRT2 KO mice American journal of physiology. Gastrointestinal and liver physiology Medium 27125275

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 441 22014574
2013 SIRT1 and SIRT2: emerging targets in neurodegeneration. EMBO molecular medicine 335 23417962
2017 SIRT2 Acts as a Cardioprotective Deacetylase in Pathological Cardiac Hypertrophy. Circulation 271 28947430
2019 SIRT2: Controversy and multiple roles in disease and physiology. Ageing research reviews 212 31505260
2014 SIRT2 induces the checkpoint kinase BubR1 to increase lifespan. The EMBO journal 195 24825348
2017 Sirtinol promotes PEPCK1 degradation and inhibits gluconeogenesis by inhibiting deacetylase SIRT2. Scientific reports 190 28127057
2018 Lysine benzoylation is a histone mark regulated by SIRT2. Nature communications 180 30154464
2012 The histone deacetylase SIRT2 stabilizes Myc oncoproteins. Cell death and differentiation 175 23175188
2021 SIRT1 and SIRT2 Activity Control in Neurodegenerative Diseases. Frontiers in pharmacology 134 33597872
2014 Oxidative stress activates SIRT2 to deacetylate and stimulate phosphoglycerate mutase. Cancer research 127 24786789
2014 SIRT2 deficiency modulates macrophage polarization and susceptibility to experimental colitis. PloS one 115 25072851
2020 Sirt2 Inhibition Enhances Metabolic Fitness and Effector Functions of Tumor-Reactive T Cells. Cell metabolism 111 32768387
2009 SIRT2-mediated protein deacetylation: An emerging key regulator in brain physiology and pathology. European journal of cell biology 106 20004495
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 105 24334550
2016 SIRT2 activates G6PD to enhance NADPH production and promote leukaemia cell proliferation. Scientific reports 101 27586085
2014 Drosophila Sirt2/mammalian SIRT3 deacetylates ATP synthase β and regulates complex V activity. The Journal of cell biology 91 25023514
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 84 32449165
2013 SIRT2: tumour suppressor or tumour promoter in operable breast cancer? European journal of cancer (Oxford, England : 1990) 82 24183459
2019 Review of the anti-inflammatory effect of SIRT1 and SIRT2 modulators on neurodegenerative diseases. European journal of pharmacology 81 31812544
2018 Sirt2 facilitates hepatic glucose uptake by deacetylating glucokinase regulatory protein. Nature communications 80 29296001
2014 SIRT2 Regulates LPS-Induced Renal Tubular CXCL2 and CCL2 Expression. Journal of the American Society of Nephrology : JASN 78 25349202
2023 SIRT2 regulates extracellular vesicle-mediated liver-bone communication. Nature metabolism 66 37188819
2018 Infection Reveals a Modification of SIRT2 Critical for Chromatin Association. Cell reports 62 29694890
2019 Sirtuins in Alzheimer's Disease: SIRT2-Related GenoPhenotypes and Implications for PharmacoEpiGenetics. International journal of molecular sciences 61 30871086
2020 The Clinical Significance of SIRT2 in Malignancies: A Tumor Suppressor or an Oncogene? Frontiers in oncology 60 33014852
2023 SIRT2 counteracts primate cardiac aging via deacetylation of STAT3 that silences CDKN2B. Nature aging 59 37783815
2015 Chronic stress and antidepressant induced changes in Hdac5 and Sirt2 affect synaptic plasticity. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology 59 26433268
2021 SIRT2 regulates mitochondrial dynamics and reprogramming via MEK1-ERK-DRP1 and AKT1-DRP1 axes. Cell reports 56 34965411
2022 Multiple Roles of SIRT2 in Regulating Physiological and Pathological Signal Transduction. Genetics research 54 36101744
2020 SIRT2 Contributes to the Regulation of Intestinal Cell Proliferation and Differentiation. Cellular and molecular gastroenterology and hepatology 52 31954883
2022 Colchicine Ameliorates Dilated Cardiomyopathy Via SIRT2-Mediated Suppression of NLRP3 Inflammasome Activation. Journal of the American Heart Association 50 35766262
2018 MicroRNA-140-5p aggravates hypertension and oxidative stress of atherosclerosis via targeting Nrf2 and Sirt2. International journal of molecular medicine 49 30483753
2015 Resveratrol Induced Premature Senescence Is Associated with DNA Damage Mediated SIRT1 and SIRT2 Down-Regulation. PloS one 49 25924011
2022 Inhibition of SIRT2 promotes APP acetylation and ameliorates cognitive impairment in APP/PS1 transgenic mice. Cell reports 47 35830807
2021 Sirtuin 2 (SIRT2): Confusing Roles in the Pathophysiology of Neurological Disorders. Frontiers in neuroscience 45 34108853
2019 A Small-Molecule SIRT2 Inhibitor That Promotes K-Ras4a Lysine Fatty-Acylation. ChemMedChem 45 30734528
2016 Downregulation of NAD-Dependent Deacetylase SIRT2 Protects Mouse Brain Against Ischemic Stroke. Molecular neurobiology 45 27796760
2011 The QKI-PLP pathway controls SIRT2 abundance in CNS myelin. Glia 45 21948283
2021 SIRT2-mediated deacetylation and deubiquitination of C/EBPβ prevents ethanol-induced liver injury. Cell discovery 44 34642310
2017 RNA-binding Protein Quaking Stabilizes Sirt2 mRNA during Oligodendroglial Differentiation. The Journal of biological chemistry 43 28188285
2016 Inhibition of SIRT2 suppresses hepatic fibrosis. American journal of physiology. Gastrointestinal and liver physiology 42 27125275
2016 HSPB1 Enhances SIRT2-Mediated G6PD Activation and Promotes Glioma Cell Proliferation. PloS one 42 27711253
2017 Sirt2-BubR1 acetylation pathway mediates the effects of advanced maternal age on oocyte quality. Aging cell 39 29067790
2023 Deacetylation of Septin4 by SIRT2 (Silent Mating Type Information Regulation 2 Homolog-2) Mitigates Damaging of Hypertensive Nephropathy. Circulation research 38 36786216
2019 SIRT2 functions in aging, autophagy, and apoptosis in post-maturation bovine oocytes. Life sciences 38 31295472
2018 Novel small molecule SIRT2 inhibitors induce cell death in leukemic cell lines. BMC cancer 38 30081901
2020 Simultaneous Inhibition of SIRT2 Deacetylase and Defatty-Acylase Activities via a PROTAC Strategy. ACS medicinal chemistry letters 37 33214845
2018 HBx-elevated SIRT2 promotes HBV replication and hepatocarcinogenesis. Biochemical and biophysical research communications 37 29366781
2018 Inhibition of SIRT2 Alleviates Fibroblast Activation and Renal Tubulointerstitial Fibrosis via MDM2. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 37 29614506
2016 SIRT2 inhibits non-small cell lung cancer cell growth through impairing Skp2-mediated p27 degradation. Oncotarget 36 26942878
2016 Identification of a Selective SIRT2 Inhibitor and Its Anti-breast Cancer Activity. Biological & pharmaceutical bulletin 34 27725455
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 30 34028177
2019 The SIRT2/cMYC Pathway Inhibits Peroxidation-Related Apoptosis In Cholangiocarcinoma Through Metabolic Reprogramming. Neoplasia (New York, N.Y.) 30 30933885
2020 SIRT2 inhibits oxidative stress and inflammatory response in diabetic osteoarthritis. European review for medical and pharmacological sciences 29 32271403
2020 Cortactin deacetylation by HDAC6 and SIRT2 regulates neuronal migration and dendrite morphogenesis during cerebral cortex development. Molecular brain 29 32711564
2023 Development of First-in-Class Dual Sirt2/HDAC6 Inhibitors as Molecular Tools for Dual Inhibition of Tubulin Deacetylation. Journal of medicinal chemistry 28 37902787
2022 Sirt2 promotes white matter oligodendrogenesis during development and in models of neonatal hypoxia. Nature communications 28 35970992
2024 NAD+ precursors promote the restoration of spermatogenesis in busulfan-treated mice through inhibiting Sirt2-regulated ferroptosis. Theranostics 27 38646657
2023 SIRT2 negatively regulates the cGAS-STING pathway by deacetylating G3BP1. EMBO reports 27 37870259
2020 SIRT2 suppresses expression of inflammatory factors via Hsp90-glucocorticoid receptor signalling. Journal of cellular and molecular medicine 27 32515550
2014 Development and characterization of 3-(benzylsulfonamido)benzamides as potent and selective SIRT2 inhibitors. European journal of medicinal chemistry 27 24602787
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 24 37728319
2023 SIRT2 alleviated renal fibrosis by deacetylating SMAD2 and SMAD3 in renal tubular epithelial cells. Cell death & disease 24 37777567
2024 FBXO31 is upregulated by METTL3 to promote pancreatic cancer progression via regulating SIRT2 ubiquitination and degradation. Cell death & disease 23 38216561
2022 The deacetylase SIRT2 contributes to autoimmune disease pathogenesis by modulating IL-17A and IL-2 transcription. Cellular & molecular immunology 23 35523941
2021 Inhibition of Sirt2 Alleviates Fibroblasts Activation and Pulmonary Fibrosis via Smad2/3 Pathway. Frontiers in pharmacology 23 34925016
2019 Recent Progress on the Discovery of Sirt2 Inhibitors for the Treatment of Various Cancers. Current topics in medicinal chemistry 23 31074370
2022 Cold exposure-induced endoplasmic reticulum stress regulates autophagy through the SIRT2/FoxO1 signaling pathway. Journal of cellular physiology 22 35938526
2021 Pharmacological Advantage of SIRT2-Selective versus pan-SIRT1-3 Inhibitors. ACS chemical biology 22 34139124
2022 SIRT2 promotes the viability, invasion and metastasis of osteosarcoma cells by inhibiting the degradation of Snail. Cell death & disease 21 36344502
2020 Discovery of Selective SIRT2 Inhibitors as Therapeutic Agents in B-Cell Lymphoma and Other Malignancies. Molecules (Basel, Switzerland) 20 31973227
2019 Pharmacophore modeling and virtual screening studies to identify novel selective SIRT2 inhibitors. Journal of molecular graphics & modelling 20 30870650
2024 Nampt/SIRT2/LDHA pathway-mediated lactate production regulates follicular dysplasia in polycystic ovary syndrome. Free radical biology & medicine 18 39489197
2023 In silico drug discovery of SIRT2 inhibitors from natural source as anticancer agents. Scientific reports 18 36750593
2022 The SIRT2 Pathway Is Involved in the Antiproliferative Effect of Flavanones in Human Leukemia Monocytic THP-1 Cells. Biomedicines 18 36289647
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
2017 Functional genetic variants within the SIRT2 gene promoter in acute myocardial infarction. PloS one 18 28445509
2017 SIRT2 and glycolytic enzyme acetylation in pluripotent stem cells. Nature cell biology 18 28446816
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 17 38648480
2023 PGAM5 deacetylation mediated by SIRT2 facilitates lipid metabolism and liver cancer proliferation. Acta biochimica et biophysica Sinica 17 37580952
2020 COXIV and SIRT2-mediated G6PD deacetylation modulate ROS homeostasis to extend pupal lifespan. The FEBS journal 17 33058529
2020 ROS-Induced SIRT2 Upregulation Contributes to Cisplatin Sensitivity in Ovarian Cancer. Antioxidants (Basel, Switzerland) 17 33207824
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
2022 SIRT2 Promotes HBV Transcription and Replication by Targeting Transcription Factor p53 to Increase the Activities of HBV Enhancers and Promoters. Frontiers in microbiology 16 35663860
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
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 15 38763011
2022 SIRT2 Deficiency Exacerbates Hepatic Steatosis via a Putative Role of the ER Stress Pathway. International journal of molecular sciences 15 35743232
2020 Correlation Between SIRT2 3'UTR Gene Polymorphism and the Susceptibility to Alzheimer's Disease. Journal of molecular neuroscience : MN 15 32124252
2022 Promotion of Lung Cancer Metastasis by SIRT2-Mediated Extracellular Protein Deacetylation. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 14 36453571