{"gene":"SIRT2","run_date":"2026-06-10T07:46:32","timeline":{"discoveries":[{"year":2011,"finding":"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.","method":"Mouse knockout model, biochemical deacetylation assays, mitotic phenotype analysis","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with defined molecular mechanism (deacetylation of CDH1/CDC20), replicated in multiple experimental contexts including in vivo tumorigenesis","pmids":["22014574"],"is_preprint":false},{"year":2007,"finding":"SIRT2 directly interacts with and deacetylates FOXO1, modulating insulin-stimulated phosphorylation and nuclear/cytosolic localization of FOXO1 to regulate adipocyte differentiation.","method":"Co-immunoprecipitation, overexpression and knockdown in 3T3-L1 cells, acetylation/phosphorylation assays","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct interaction shown by Co-IP, functional consequence (adipogenesis) established by gain- and loss-of-function, single lab with multiple orthogonal methods","pmids":["17681146"],"is_preprint":false},{"year":2014,"finding":"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.","method":"In vivo overexpression, NAD+ precursor (NMN) treatment, site-specific acetylation analysis, lifespan measurement in mouse models","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple in vivo models, site-specific acetylation mapping, functional rescue, identifies acetyltransferase (CBP) counterpart","pmids":["24825348"],"is_preprint":false},{"year":2014,"finding":"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.","method":"In vitro deacetylation assay, site-directed mutagenesis (K100Q acetylation mimetic), Co-IP, ROS stimulation experiments","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro assay with active-site mutagenesis, functional rescue, mechanistic pathway established in single rigorous study","pmids":["24786789"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Co-IP, overexpression/knockdown, site-specific deacetylation assays, ubiquitination assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct interaction shown, specific lysine identified, downstream hydroxylation/ubiquitination demonstrated with multiple orthogonal methods","pmids":["24681946"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Shotgun mass spectrometry, site-directed mutagenesis, biochemical tetramerization assay, metabolic flux analysis, xenograft model","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — site identified by MS, functional mutagenesis confirming mechanism, in vivo tumor model, single lab with multiple orthogonal methods","pmids":["27197174"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Deacetylation assay, site-directed mutagenesis (K403), enzymatic activity measurement, knockdown/overexpression in AML cell lines","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — site-specific deacetylation demonstrated, enzymatic activity assay, functional cellular phenotype, multiple methods","pmids":["27586085"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Sirt2 knockout mouse, acetylation/ubiquitination assays, surface receptor trafficking assay, electrophysiology, behavioral tests","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout mouse with mechanistic pathway (deacetylation competing with ubiquitination), functional synaptic/behavioral readout, multiple orthogonal methods","pmids":["28793258"],"is_preprint":false},{"year":2017,"finding":"SIRT2 binds to and deacetylates LKB1 at lysine 48, promoting LKB1 phosphorylation and subsequent activation of LKB1-AMPK signaling, thereby protecting against cardiac hypertrophy.","method":"Co-IP, deacetylation assay, phosphorylation analysis, cardiac-specific transgenic and knockout mouse models, in vitro cardiomyocyte experiments","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding and site-specific deacetylation shown, downstream kinase activation confirmed, validated in both KO and transgenic in vivo models","pmids":["28947430"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Co-IP, confocal microscopy, SIRT2 knockout mouse, NFAT luciferase reporter, pharmacological NFAT inhibition rescue","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, nuclear localization assay, genetic rescue with pharmacological NFAT inhibition, multiple methods in single study","pmids":["29440391"],"is_preprint":false},{"year":2018,"finding":"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.","method":"In vivo overexpression/knockdown in mouse liver, deacetylation-mimicking and acetylation-mimicking GKRP mutants, glucose tolerance tests, Co-IP","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — site-specific deacetylation with functional mimetics, in vivo metabolic phenotype, multiple diabetic mouse models","pmids":["29296001"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Phosphoproteomics, site-directed mutagenesis (S25), subcellular fractionation, Co-IP, H3K18 deacetylation assay, infection model","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — phosphoproteomics site mapping, mutagenesis confirming functional relevance, phosphatase complex identified by Co-IP, functional chromatin association demonstrated","pmids":["29694890"],"is_preprint":false},{"year":2013,"finding":"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.","method":"siRNA knockdown in mouse oocytes, confocal microscopy, overexpression rescue, immunoblotting","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined substrate targets (H4K16ac, α-tubulin), specific meiotic phenotype, single lab","pmids":["24334550"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Knockdown, site-directed mutagenesis (K243Q, K243R), microinjection in mouse oocytes, confocal microscopy","journal":"Aging cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — site-specific mutagenesis with functional rescue, genetic epistasis established between Sirt2 and BubR1-K243 in oocyte meiosis","pmids":["29067790"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Co-IP, site-specific mutagenesis, enzymatic activity assays, in vitro and in vivo invasion/migration assays","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — site-specific deacetylation with functional mutants, enzymatic activity measured, downstream pathway (HIF1α-SRC) characterized","pmids":["32141187"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Sirt2 knockout mouse T cells, metabolomics, Seahorse metabolic flux assay, pharmacological inhibition of SIRT2, tumor infiltrating lymphocyte analysis","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with metabolic phenotype confirmed by multiple metabolic flux methods, replicated with pharmacological inhibition","pmids":["32768387"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Acetylation assays, site-directed mutagenesis, Co-IP, mitochondrial morphology analysis, metabolic flux assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — site-specific acetylation mapping on MEK1 and AKT1, two parallel pathways identified with functional validation, single lab with multiple orthogonal methods","pmids":["34965411"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Co-IP, site-specific deacetylation assays, ubiquitination assay, liver-specific knockout and transgenic mice, in vivo ethanol model","journal":"Cell discovery","confidence":"High","confidence_rationale":"Tier 2 / Strong — site-specific deacetylation-ubiquitination switch demonstrated, both KO and transgenic in vivo models used, mechanistic pathway fully defined","pmids":["34642310"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Co-IP, deacetylation assay, site-directed mutagenesis, HR reporter assay, foci formation at DNA damage sites, nuclear fractionation","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct interaction, site-specific deacetylation, functional HR assay, and downstream localization all shown in single rigorous study","pmids":["33789098"],"is_preprint":false},{"year":2021,"finding":"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.","method":"In vitro enzymatic assay, mass spectrometry, antibody-based detection, biochemical characterization of writer (HAT1) and eraser (SIRT2)","journal":"Cell discovery","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic reconstitution, chemical validation, identification of both writer and eraser enzymes","pmids":["34961760"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Genetic deletion and pharmacological inhibition of SIRT2, site-specific acetylation mapping, primary neuron protection assay, APP/PS1 mouse model behavioral testing","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — site-specific deacetylation identified, functional processing assay, in vivo rescue in AD mouse model with both genetic and pharmacological approaches","pmids":["35830807"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Co-IP, deacetylation assay, site-directed mutagenesis, ubiquitination assay, renal tubule-specific KO and overexpression in vivo models","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — site-specific deacetylation with downstream ubiquitination-degradation mechanism, E3 ligase (SMURF2) identified, both in vitro and in vivo validation","pmids":["37777567"],"is_preprint":false},{"year":2023,"finding":"SIRT2 deacetylates septin4 at K174, inhibiting the cleaved-PARP1-cleaved-caspase3 apoptosis pathway in renal podocytes and mitigating angiotensin II-induced hypertensive nephropathy.","method":"Immunoprecipitation, mass spectrometry, site-directed mutagenesis (K174Q/R), SIRT2 transgenic and knockout mice, proteomic/acetyl-proteomic analysis","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — site-specific deacetylation identified by MS, confirmed with functional mutants in vivo and in vitro, downstream apoptosis pathway defined","pmids":["36786216"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Co-IP, site-directed mutagenesis, cGAS activity assays, AGK2 pharmacological inhibition, HSV-1 infection mouse model","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — site-specific deacetylation shown, functional consequence on cGAS complex demonstrated, in vivo infection model, multiple orthogonal methods","pmids":["37870259"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Proteomic analysis of primate hearts, SIRT2-deficient human pluripotent stem cell-derived cardiomyocytes, lentiviral SIRT2 overexpression in aged mice, acetylation assays","journal":"Nature aging","confidence":"High","confidence_rationale":"Tier 2 / Strong — primate and human iPSC models, mechanistic axis (SIRT2-STAT3-CDKN2B) defined, in vivo rescue experiment, multiple orthogonal methods","pmids":["37783815"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Co-IP, chromatin immunoprecipitation, site-directed mutagenesis (S46A, S53A), BER reporter assay, oxidative stress treatment","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct interaction shown, phosphorylation sites mapped, ChIP demonstrating OGG1 promoter binding, functional BER assay, multiple methods","pmids":["38554113"],"is_preprint":false},{"year":2019,"finding":"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.","method":"In vitro deacylation assay, fatty acylation detection, plasma membrane localization assay, Co-IP, cell migration assay","journal":"ChemMedChem / ACS chemical biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic deacylation, site-specific mutagenesis, functional localization and effector recruitment shown, two independent studies","pmids":["30734528","31433161"],"is_preprint":false},{"year":2011,"finding":"SIRT2 and HDAC6 act synergistically to deacetylate cortactin, promoting bladder cancer cell migration and invasion. Cortactin is a substrate of SIRT2.","method":"siRNA knockdown, HDAC6 inhibitor (tubacin), migration and invasion assays","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional migration assay with siRNA, substrate identity implied but no direct deacetylation assay described in abstract","pmids":["22089141"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Co-IP, Western blot, siRNA knockdown, adenoviral overexpression, Sirt2 KO mouse model","journal":"Journal of the American Society of Nephrology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — interaction shown by Co-IP, acetylation of MKP-1 detected, downstream signaling measured, but direct deacetylation site not defined in abstract","pmids":["25349202"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Overexpression, knockdown, chromatin immunoprecipitation, acetylation assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — ChIP showing reduced p65 promoter binding, deacetylation of p65 at K310 shown, functional rescue with miR-21 knockdown, single lab","pmids":["24161395"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Co-IP, deacetylation assay, SIRT2 overexpression/knockdown, proteasome inhibitor, lung cancer specimens","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct interaction by Co-IP, deacetylation-degradation link shown, functional p27 consequence, single lab","pmids":["26942878"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Co-IP, Western blot, immunohistochemistry, STZ diabetic rat model, SIRT2 overexpression in cardiomyocytes","journal":"European journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP interaction shown, α-tubulin deacetylation functional consequence demonstrated in disease model, single lab","pmids":["26209361"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Co-IP, mutation analysis (K294), GRE-reporter assay, overexpression/knockdown, LPS stimulation","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — site-specific mutagenesis at K294, GR translocation confirmed, functional cytokine reporter assay, single lab","pmids":["32515550"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Co-IP, site-directed mutagenesis, chaperone activity assay, apoptosis assay, mitophagy analysis","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct interaction and site-specific acetylation shown, functional chaperone alteration demonstrated, single lab","pmids":["30352233"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Co-IP, ubiquitination assay, actin polymerization assay, SIRT2 overexpression/knockdown","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct interaction shown by Co-IP, acetylation-ubiquitination coupling shown, functional actin/migration assay, single lab","pmids":["29908203"],"is_preprint":false},{"year":2013,"finding":"ERK1/2 interacts with SIRT2 (exogenous and endogenous) and increases SIRT2 protein levels, stability, and deacetylase activity.","method":"Co-IP, deacetylase activity assay, MEK inhibitor (U0126), constitutively active MEK overexpression","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP, functional deacetylase activity regulation shown, single lab with two methods","pmids":["23806683"],"is_preprint":false},{"year":2014,"finding":"c-Src kinase interacts with and phosphorylates SIRT2 at Tyr104, modulating SIRT2 protein levels (decreasing them) and regulating SIRT2 deacetylase activity.","method":"Co-IP, site-directed mutagenesis, Src inhibitor (SU6656), siRNA knockdown of c-Src, deacetylase activity assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct interaction and phosphorylation site (Y104) identified, functional deacetylase activity effect shown, single lab","pmids":["24996174"],"is_preprint":false},{"year":2021,"finding":"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.","method":"I-SceI-based GFP HR reporter assay, siRNA depletion, RAD51 and RPA1 foci analysis","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — established epistasis in DSB repair by reporter assay and foci analysis, but mechanism of SIRT2 action (substrate not clearly defined) partially unclear","pmids":["33624391"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Site-directed mutagenesis, deacetylation assay on P38, siRNA, xenograft, pharmacological inhibitor (AK-7) resistance assay","journal":"Neoplasia","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — SUMO site mapping with functional validation, new substrate (P38) identified, single lab","pmids":["33316537"],"is_preprint":false},{"year":2021,"finding":"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.","method":"SIRT2 knockout rat, metabolomics, adenoviral overexpression, immunoprecipitation, insulin secretion assay","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO rat with metabolic phenotype, deacetylation assay on GKRP, Co-IP for protein interaction, single lab","pmids":["33754030"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Co-IP, deacetylase-inactive mutant, knockdown/overexpression, xenograft metastasis model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP interaction, deacetylase activity requirement shown with catalytic mutant, in vivo metastasis assay, single lab","pmids":["36344502"],"is_preprint":false},{"year":2022,"finding":"SIRT2 mediates PGAM5 deacetylation to activate malic enzyme 1 (ME1) activity (via ME1 dephosphorylation), promoting lipid synthesis and liver cancer cell proliferation.","method":"Immunoprecipitation, mass spectrometry, enzymatic activity assay, overexpression/knockdown","journal":"Acta biochimica et biophysica Sinica","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — MS identification, enzymatic activity assay, functional proliferation assay, single lab","pmids":["37580952"],"is_preprint":false},{"year":2023,"finding":"SIRT2 deacetylates ACLY (ATP citrate lyase) in esophageal squamous cell carcinoma cells, promoting ACLY activity, lipid synthesis, and cancer cell proliferation and migration.","method":"Co-IP, AGK2 pharmacological inhibition, acetylation assay, overexpression rescue, xenograft model","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — interaction shown by Co-IP, acetylation change demonstrated, functional rescue, single lab","pmids":["38426936"],"is_preprint":false},{"year":2023,"finding":"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.","method":"TLR activation, autophagy flux analysis, extracellular deacetylation assay, site-specific acetylation detection in lung cancer patient serum","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — novel extracellular localization and activity shown, site-specific deacetylation demonstrated, patient sample correlation, single lab","pmids":["36453571"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Co-IP, SIRT2-specific inhibitor, deacetylation assay, overexpression/knockdown, in vivo embryo implantation assay","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP interaction, SIRT2 inhibitor functional test, in vivo mouse model, single lab","pmids":["36418297"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Co-IP, site-specific acetylation assay (K394), knockdown and pharmacological inhibition of SIRT2, LAP and phagocytosis assays, in vivo sepsis mouse model","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — site-specific deacetylation identified, functional downstream Atg4B-LC3-LAP pathway established, in vivo validation, single lab","pmids":["36865524"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Co-IP, nuclear fractionation, ChIP, overexpression in OPCs, neonatal hypoxia mouse model","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — interaction and nuclear localization shown, genomic binding by ChIP demonstrated, functional rescue of OL maturation, single lab","pmids":["35970992"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Cardiomyocyte-specific Sirt2 knockout, Nrf2 double-knockout epistasis, NRF2 activity/protein level assays, cardiac functional measurements","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (Sirt2 KO x Nrf2 KO), NRF2 mechanistic link established, but molecular details of SIRT2-NRF2 interaction not fully specified in abstract","pmids":["37728319"],"is_preprint":false},{"year":2017,"finding":"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.","method":"RNA pulldown, QRE mutagenesis, mRNA half-life assay, QKI overexpression, qk viable mutant mouse","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct mRNA-protein interaction shown, transcript half-life measured, single lab","pmids":["28188285"],"is_preprint":false},{"year":2024,"finding":"FBXO31, an F-box protein, interacts with SIRT2 and promotes proteasome-dependent degradation of SIRT2, binding to the sirtuin-type domain of SIRT2.","method":"Co-IP, protein half-life assay, ubiquitination assay, domain mapping, cancer cell xenograft","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP with domain mapping, ubiquitination and half-life assays, single lab","pmids":["38216561"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Co-IP, deacetylation activity assay, GARS mutation analysis, Drosophila genetic rescue model","journal":"Aging cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction and functional inhibition of SIRT2 activity shown, genetic epistasis in Drosophila model, multiple methods, single lab","pmids":["34053152"],"is_preprint":false},{"year":2024,"finding":"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.","method":"PROTAC degrader, pharmacological inhibitors (TM, AGK2), E-cadherin endocytosis assay, Sirt2 knockout mouse, IBD mouse model","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway (Arf6-E-cadherin endocytosis) identified, PROTAC vs. inhibitor comparison reveals activity-specific mechanism, single lab with multiple orthogonal approaches","pmids":["38648480"],"is_preprint":false}],"current_model":"SIRT2 is a predominantly cytoplasmic NAD+-dependent deacetylase (and defatty-acylase) that regulates diverse cellular processes—including mitosis (via CDH1/CDC20/APC-C and BubR1 deacetylation), glucose and lipid metabolism (PGAM2, PKM2, G6PD, IDH1, LKB1-AMPK, GKRP deacetylation), genome integrity (BRCA1-BARD1 heterodimerization, OGG1-dependent BER, HR), cytoskeletal dynamics (α-tubulin, cortactin), innate immunity (G3BP1/cGAS-STING, NF-κB/p65), cardiac homeostasis (NFATc2, STAT3, NRF2), and neurodegeneration (APP, AMPAR, α-tubulin)—through site-specific lysine deacetylation of a broad spectrum of substrates; its activity is regulated by post-translational modifications including ERK1/2-mediated stabilization, c-Src-mediated phosphorylation at Y104, ATM/ATR-mediated phosphorylation at S46/S53, SUMOylation at K183/K340, and S25 dephosphorylation by PPM1A/PPM1B that controls chromatin relocalization."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2007,"claim":"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","pmids":["17681146"],"confidence":"High","gaps":["Specific lysine sites on FOXO1 not mapped","Relationship between deacetylation and insulin-stimulated phosphorylation not fully resolved"]},{"year":2011,"claim":"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","pmids":["22014574"],"confidence":"High","gaps":["Acetylation sites on CDH1/CDC20 not specified","Direct effect on APC/C catalytic activity inferred from substrate levels"]},{"year":2013,"claim":"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","pmids":["24161395","24334550"],"confidence":"Medium","gaps":["Tissue-specificity of p65 regulation unclear","Direct vs indirect effects on tubulin acetylation not fully separated"]},{"year":2014,"claim":"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","pmids":["24786789","24681946","23806683","24996174"],"confidence":"Medium","gaps":["Integration of opposing ERK and Src inputs on a single SIRT2 pool unresolved","Physiological stimuli controlling these PTMs not fully defined"]},{"year":2014,"claim":"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","pmids":["24825348"],"confidence":"High","gaps":["Whether BubR1 stabilization fully accounts for lifespan effects unclear","CBP/SIRT2 competition kinetics not quantified"]},{"year":2016,"claim":"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","pmids":["27197174","27586085"],"confidence":"High","gaps":["Context-dependence across tumor types not delineated","Net metabolic output integrating multiple enzyme targets not modeled"]},{"year":2017,"claim":"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","pmids":["28947430","28793258","28188285"],"confidence":"High","gaps":["Cross-talk between metabolic and trafficking substrates in single cell types unresolved","How tissue-specific substrate selection is achieved unclear"]},{"year":2018,"claim":"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","pmids":["29694890","29296001","29440391"],"confidence":"High","gaps":["Signals coupling infection to phosphatase activation incompletely defined","Genome-wide chromatin targets of relocalized SIRT2 not catalogued"]},{"year":2019,"claim":"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","pmids":["30734528","31433161"],"confidence":"High","gaps":["Relative cellular contribution of deacylase vs deacetylase activity unquantified","Acyl-substrate spectrum incompletely mapped"]},{"year":2020,"claim":"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","pmids":["32768387","33316537","32141187"],"confidence":"High","gaps":["Mechanism by which SUMOylation redirects substrate choice unclear","In vivo immunometabolic targets in human T cells not fully defined"]},{"year":2021,"claim":"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","pmids":["33789098","33624391","34053152","34642310"],"confidence":"High","gaps":["Whether HR roles depend on catalytic activity for all targets unclear","Coordination of repair and mitotic functions of the same pool unresolved"]},{"year":2022,"claim":"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","pmids":["35830807","37777567"],"confidence":"High","gaps":["Whether deacetylation directly primes ubiquitination or acts indirectly not fully resolved","Neuronal vs systemic contributions to cognitive rescue not separated"]},{"year":2023,"claim":"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","pmids":["37870259","37783815","37728319","36786216"],"confidence":"High","gaps":["Direct molecular nature of SIRT2-NRF2 regulation not specified","Balance between protective and detrimental cardiac roles context-dependent"]},{"year":2024,"claim":"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","pmids":["38554113","38648480"],"confidence":"Medium","gaps":["Catalytic-independent scaffolding functions not systematically mapped","Distinct in vivo consequences of inhibition vs degradation not generalized across tissues"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,3,5,6,7,8,10,14,18,20,21,22,23,26]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,5,19,26]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,5,6,8,14,17,21]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[11,46]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[11,25,46]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[18,46]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[12,31]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[43]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,2,13]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[3,5,6,10,14,15,39]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[18,25,37]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[15,23]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8,9,21,24]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[17,21,30,49]}],"complexes":["BRCA1-BARD1"],"partners":["BRCA1","BARD1","OGG1","G3BP1","LKB1","NFATC2","FOXO1","HIF1A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IXJ6","full_name":"NAD-dependent protein deacetylase sirtuin-2","aliases":["NAD-dependent protein deacylase sirtuin-2","NAD-dependent protein defatty-acylase sirtuin-2","Regulatory protein SIR2 homolog 2","SIR2-like protein 2"],"length_aa":389,"mass_kda":43.2,"function":"NAD-dependent protein deacetylase, which deacetylates internal lysines on histone and alpha-tubulin as well as many other proteins such as key transcription factors (PubMed:12620231, PubMed:16648462, PubMed:18249187, PubMed:18332217, PubMed:18995842, PubMed:20543840, PubMed:20587414, PubMed:21081649, PubMed:21726808, PubMed:21949390, PubMed:22014574, PubMed:22771473, PubMed:23468428, PubMed:23908241, PubMed:24177535, PubMed:24681946, PubMed:24769394, PubMed:24940000). Participates in the modulation of multiple and diverse biological processes such as cell cycle control, genomic integrity, microtubule dynamics, cell differentiation, metabolic networks, and autophagy (PubMed:12620231, PubMed:16648462, PubMed:18249187, PubMed:18332217, PubMed:18995842, PubMed:20543840, PubMed:20587414, PubMed:21081649, PubMed:21726808, PubMed:21949390, PubMed:22014574, PubMed:22771473, PubMed:23468428, PubMed:23908241, PubMed:24177535, PubMed:24681946, PubMed:24769394, PubMed:24940000). Plays a major role in the control of cell cycle progression and genomic stability (PubMed:12697818, PubMed:16909107, PubMed:17488717, PubMed:17726514, PubMed:19282667, PubMed:23468428). Functions in the antephase checkpoint preventing precocious mitotic entry in response to microtubule stress agents, and hence allowing proper inheritance of chromosomes (PubMed:12697818, PubMed:16909107, PubMed:17488717, PubMed:17726514, PubMed:19282667, PubMed:23468428). Positively regulates the anaphase promoting complex/cyclosome (APC/C) ubiquitin ligase complex activity by deacetylating CDC20 and FZR1, then allowing progression through mitosis (PubMed:22014574). Associates both with chromatin at transcriptional start sites (TSSs) and enhancers of active genes (PubMed:23468428). Plays a role in cell cycle and chromatin compaction through epigenetic modulation of the regulation of histone H4 'Lys-20' methylation (H4K20me1) during early mitosis (PubMed:23468428). Specifically deacetylates histone H4 at 'Lys-16' (H4K16ac) between the G2/M transition and metaphase enabling H4K20me1 deposition by KMT5A leading to ulterior levels of H4K20me2 and H4K20me3 deposition throughout cell cycle, and mitotic S-phase progression (PubMed:23468428). Deacetylates KMT5A modulating KMT5A chromatin localization during the mitotic stress response (PubMed:23468428). Also deacetylates histone H3 at 'Lys-57' (H3K56ac) during the mitotic G2/M transition (PubMed:20587414). Upon bacterium Listeria monocytogenes infection, deacetylates 'Lys-18' of histone H3 in a receptor tyrosine kinase MET- and PI3K/Akt-dependent manner, thereby inhibiting transcriptional activity and promoting late stages of listeria infection (PubMed:23908241). During oocyte meiosis progression, may deacetylate histone H4 at 'Lys-16' (H4K16ac) and alpha-tubulin, regulating spindle assembly and chromosome alignment by influencing microtubule dynamics and kinetochore function (PubMed:24940000). Deacetylates histone H4 at 'Lys-16' (H4K16ac) at the VEGFA promoter and thereby contributes to regulate expression of VEGFA, a key regulator of angiogenesis (PubMed:24940000). Deacetylates alpha-tubulin at 'Lys-40' and hence controls neuronal motility, oligodendroglial cell arbor projection processes and proliferation of non-neuronal cells (PubMed:18332217, PubMed:18995842). Phosphorylation at Ser-368 by a G1/S-specific cyclin E-CDK2 complex inactivates SIRT2-mediated alpha-tubulin deacetylation, negatively regulating cell adhesion, cell migration and neurite outgrowth during neuronal differentiation (PubMed:17488717). Deacetylates PARD3 and participates in the regulation of Schwann cell peripheral myelination formation during early postnatal development and during postinjury remyelination (PubMed:21949390). Involved in several cellular metabolic pathways (PubMed:20543840, PubMed:21726808, PubMed:24769394). Plays a role in the regulation of blood glucose homeostasis by deacetylating and stabilizing phosphoenolpyruvate carboxykinase PCK1 activity in response to low nutrient availability (PubMed:21726808). Acts as a key regulator in the pentose phosphate pathway (PPP) by deacetylating and activating the glucose-6-phosphate G6PD enzyme, and therefore, stimulates the production of cytosolic NADPH to counteract oxidative damage (PubMed:24769394). Maintains energy homeostasis in response to nutrient deprivation as well as energy expenditure by inhibiting adipogenesis and promoting lipolysis (PubMed:20543840). Attenuates adipocyte differentiation by deacetylating and promoting FOXO1 interaction to PPARG and subsequent repression of PPARG-dependent transcriptional activity (PubMed:20543840). Plays a role in the regulation of lysosome-mediated degradation of protein aggregates by autophagy in neuronal cells (PubMed:20543840). Deacetylates FOXO1 in response to oxidative stress or serum deprivation, thereby negatively regulating FOXO1-mediated autophagy (PubMed:20543840). Deacetylates a broad range of transcription factors and co-regulators regulating target gene expression. Deacetylates transcriptional factor FOXO3 stimulating the ubiquitin ligase SCF(SKP2)-mediated FOXO3 ubiquitination and degradation (By similarity). Deacetylates HIF1A and therefore promotes HIF1A degradation and inhibition of HIF1A transcriptional activity in tumor cells in response to hypoxia (PubMed:24681946). Deacetylates RELA in the cytoplasm inhibiting NF-kappaB-dependent transcription activation upon TNF stimulation (PubMed:21081649). Inhibits transcriptional activation by deacetylating p53/TP53 and EP300 (PubMed:18249187, PubMed:18995842). Also deacetylates EIF5A (PubMed:22771473). In addition to protein deacetylase activity, also acts as a protein-lysine deacylase by recognizing other acyl groups: catalyzes removal of N(6)-benzoyl (benzoyl) and N(6)-methacryl (methacryl) acyl groups from lysine residues, leading to histone debenzoylation and demethacrylation, respectively (PubMed:30154464, PubMed:34961760). Functions as a negative regulator on oxidative stress-tolerance in response to anoxia-reoxygenation conditions (PubMed:24769394). Plays a role as tumor suppressor (PubMed:22014574). In addition to protein deacetylase activity, also has activity toward long-chain fatty acyl groups and mediates protein-lysine demyristoylation and depalmitoylation of target proteins, such as ARF6 and KRAS, thereby regulating their association with membranes (PubMed:25704306, PubMed:29239724, PubMed:32103017) Deacetylates EP300, alpha-tubulin and histone H3 and H4 Deacetylates EP300, alpha-tubulin and histone H3 and H4 Lacks deacetylation activity, at least toward known SIRT2 targets","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q8IXJ6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SIRT2","classification":"Not Classified","n_dependent_lines":11,"n_total_lines":1208,"dependency_fraction":0.009105960264900662},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SIRT2","total_profiled":1310},"omim":[{"mim_id":"604483","title":"SIRTUIN 5; SIRT5","url":"https://www.omim.org/entry/604483"},{"mim_id":"604482","title":"SIRTUIN 4; SIRT4","url":"https://www.omim.org/entry/604482"},{"mim_id":"604480","title":"SIRTUIN 2; SIRT2","url":"https://www.omim.org/entry/604480"},{"mim_id":"604479","title":"SIRTUIN 1; SIRT1","url":"https://www.omim.org/entry/604479"},{"mim_id":"602810","title":"HISTONE GENE CLUSTER 1, H3 HISTONE FAMILY, MEMBER A; HIST1H3A","url":"https://www.omim.org/entry/602810"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoli","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":492.9},{"tissue":"skeletal muscle","ntpm":306.9},{"tissue":"tongue","ntpm":203.7}],"url":"https://www.proteinatlas.org/search/SIRT2"},"hgnc":{"alias_symbol":[],"prev_symbol":["SIR2L"]},"alphafold":{"accession":"Q8IXJ6","domains":[{"cath_id":"3.40.50.1220","chopping":"56-93_144-187_240-290_307-355","consensus_level":"medium","plddt":96.3513,"start":56,"end":355},{"cath_id":"3.30.1600.10","chopping":"94-142_190-232","consensus_level":"medium","plddt":90.0963,"start":94,"end":232}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IXJ6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IXJ6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IXJ6-F1-predicted_aligned_error_v6.png","plddt_mean":81.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SIRT2","jax_strain_url":"https://www.jax.org/strain/search?query=SIRT2"},"sequence":{"accession":"Q8IXJ6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IXJ6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IXJ6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IXJ6"}},"corpus_meta":[{"pmid":"22014574","id":"PMC_22014574","title":"SIRT2 maintains genome integrity and suppresses tumorigenesis through regulating APC/C activity.","date":"2011","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/22014574","citation_count":444,"is_preprint":false},{"pmid":"17681146","id":"PMC_17681146","title":"SIRT2 regulates adipocyte differentiation through FoxO1 acetylation/deacetylation.","date":"2007","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/17681146","citation_count":406,"is_preprint":false},{"pmid":"23417962","id":"PMC_23417962","title":"SIRT1 and SIRT2: emerging targets in neurodegeneration.","date":"2013","source":"EMBO molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/23417962","citation_count":336,"is_preprint":false},{"pmid":"28947430","id":"PMC_28947430","title":"SIRT2 Acts as a Cardioprotective Deacetylase in Pathological Cardiac 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mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/33624391","citation_count":13,"is_preprint":false},{"pmid":"38426936","id":"PMC_38426936","title":"SIRT2-mediated deacetylation of ACLY promotes the progression of oesophageal squamous cell carcinoma.","date":"2024","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38426936","citation_count":13,"is_preprint":false},{"pmid":"36418297","id":"PMC_36418297","title":"FHL1 mediates HOXA10 deacetylation via SIRT2 to enhance blastocyst-epithelial adhesion.","date":"2022","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/36418297","citation_count":13,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":48784,"output_tokens":12151,"usd":0.164308,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":23365,"output_tokens":5385,"usd":0.125725,"stage2_stop_reason":"end_turn"},"total_usd":0.290033,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Mouse knockout model, biochemical deacetylation assays, mitotic phenotype analysis\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with defined molecular mechanism (deacetylation of CDH1/CDC20), replicated in multiple experimental contexts including in vivo tumorigenesis\",\n      \"pmids\": [\"22014574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SIRT2 directly interacts with and deacetylates FOXO1, modulating insulin-stimulated phosphorylation and nuclear/cytosolic localization of FOXO1 to regulate adipocyte differentiation.\",\n      \"method\": \"Co-immunoprecipitation, overexpression and knockdown in 3T3-L1 cells, acetylation/phosphorylation assays\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction shown by Co-IP, functional consequence (adipogenesis) established by gain- and loss-of-function, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"17681146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"In vivo overexpression, NAD+ precursor (NMN) treatment, site-specific acetylation analysis, lifespan measurement in mouse models\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple in vivo models, site-specific acetylation mapping, functional rescue, identifies acetyltransferase (CBP) counterpart\",\n      \"pmids\": [\"24825348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro deacetylation assay, site-directed mutagenesis (K100Q acetylation mimetic), Co-IP, ROS stimulation experiments\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro assay with active-site mutagenesis, functional rescue, mechanistic pathway established in single rigorous study\",\n      \"pmids\": [\"24786789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP, overexpression/knockdown, site-specific deacetylation assays, ubiquitination assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction shown, specific lysine identified, downstream hydroxylation/ubiquitination demonstrated with multiple orthogonal methods\",\n      \"pmids\": [\"24681946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Shotgun mass spectrometry, site-directed mutagenesis, biochemical tetramerization assay, metabolic flux analysis, xenograft model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — site identified by MS, functional mutagenesis confirming mechanism, in vivo tumor model, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"27197174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Deacetylation assay, site-directed mutagenesis (K403), enzymatic activity measurement, knockdown/overexpression in AML cell lines\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific deacetylation demonstrated, enzymatic activity assay, functional cellular phenotype, multiple methods\",\n      \"pmids\": [\"27586085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Sirt2 knockout mouse, acetylation/ubiquitination assays, surface receptor trafficking assay, electrophysiology, behavioral tests\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout mouse with mechanistic pathway (deacetylation competing with ubiquitination), functional synaptic/behavioral readout, multiple orthogonal methods\",\n      \"pmids\": [\"28793258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SIRT2 binds to and deacetylates LKB1 at lysine 48, promoting LKB1 phosphorylation and subsequent activation of LKB1-AMPK signaling, thereby protecting against cardiac hypertrophy.\",\n      \"method\": \"Co-IP, deacetylation assay, phosphorylation analysis, cardiac-specific transgenic and knockout mouse models, in vitro cardiomyocyte experiments\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding and site-specific deacetylation shown, downstream kinase activation confirmed, validated in both KO and transgenic in vivo models\",\n      \"pmids\": [\"28947430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP, confocal microscopy, SIRT2 knockout mouse, NFAT luciferase reporter, pharmacological NFAT inhibition rescue\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, nuclear localization assay, genetic rescue with pharmacological NFAT inhibition, multiple methods in single study\",\n      \"pmids\": [\"29440391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"In vivo overexpression/knockdown in mouse liver, deacetylation-mimicking and acetylation-mimicking GKRP mutants, glucose tolerance tests, Co-IP\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — site-specific deacetylation with functional mimetics, in vivo metabolic phenotype, multiple diabetic mouse models\",\n      \"pmids\": [\"29296001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Phosphoproteomics, site-directed mutagenesis (S25), subcellular fractionation, Co-IP, H3K18 deacetylation assay, infection model\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — phosphoproteomics site mapping, mutagenesis confirming functional relevance, phosphatase complex identified by Co-IP, functional chromatin association demonstrated\",\n      \"pmids\": [\"29694890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown in mouse oocytes, confocal microscopy, overexpression rescue, immunoblotting\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined substrate targets (H4K16ac, α-tubulin), specific meiotic phenotype, single lab\",\n      \"pmids\": [\"24334550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Knockdown, site-directed mutagenesis (K243Q, K243R), microinjection in mouse oocytes, confocal microscopy\",\n      \"journal\": \"Aging cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific mutagenesis with functional rescue, genetic epistasis established between Sirt2 and BubR1-K243 in oocyte meiosis\",\n      \"pmids\": [\"29067790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP, site-specific mutagenesis, enzymatic activity assays, in vitro and in vivo invasion/migration assays\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific deacetylation with functional mutants, enzymatic activity measured, downstream pathway (HIF1α-SRC) characterized\",\n      \"pmids\": [\"32141187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Sirt2 knockout mouse T cells, metabolomics, Seahorse metabolic flux assay, pharmacological inhibition of SIRT2, tumor infiltrating lymphocyte analysis\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with metabolic phenotype confirmed by multiple metabolic flux methods, replicated with pharmacological inhibition\",\n      \"pmids\": [\"32768387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Acetylation assays, site-directed mutagenesis, Co-IP, mitochondrial morphology analysis, metabolic flux assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific acetylation mapping on MEK1 and AKT1, two parallel pathways identified with functional validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"34965411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP, site-specific deacetylation assays, ubiquitination assay, liver-specific knockout and transgenic mice, in vivo ethanol model\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — site-specific deacetylation-ubiquitination switch demonstrated, both KO and transgenic in vivo models used, mechanistic pathway fully defined\",\n      \"pmids\": [\"34642310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP, deacetylation assay, site-directed mutagenesis, HR reporter assay, foci formation at DNA damage sites, nuclear fractionation\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction, site-specific deacetylation, functional HR assay, and downstream localization all shown in single rigorous study\",\n      \"pmids\": [\"33789098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro enzymatic assay, mass spectrometry, antibody-based detection, biochemical characterization of writer (HAT1) and eraser (SIRT2)\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic reconstitution, chemical validation, identification of both writer and eraser enzymes\",\n      \"pmids\": [\"34961760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Genetic deletion and pharmacological inhibition of SIRT2, site-specific acetylation mapping, primary neuron protection assay, APP/PS1 mouse model behavioral testing\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — site-specific deacetylation identified, functional processing assay, in vivo rescue in AD mouse model with both genetic and pharmacological approaches\",\n      \"pmids\": [\"35830807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP, deacetylation assay, site-directed mutagenesis, ubiquitination assay, renal tubule-specific KO and overexpression in vivo models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — site-specific deacetylation with downstream ubiquitination-degradation mechanism, E3 ligase (SMURF2) identified, both in vitro and in vivo validation\",\n      \"pmids\": [\"37777567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SIRT2 deacetylates septin4 at K174, inhibiting the cleaved-PARP1-cleaved-caspase3 apoptosis pathway in renal podocytes and mitigating angiotensin II-induced hypertensive nephropathy.\",\n      \"method\": \"Immunoprecipitation, mass spectrometry, site-directed mutagenesis (K174Q/R), SIRT2 transgenic and knockout mice, proteomic/acetyl-proteomic analysis\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — site-specific deacetylation identified by MS, confirmed with functional mutants in vivo and in vitro, downstream apoptosis pathway defined\",\n      \"pmids\": [\"36786216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP, site-directed mutagenesis, cGAS activity assays, AGK2 pharmacological inhibition, HSV-1 infection mouse model\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific deacetylation shown, functional consequence on cGAS complex demonstrated, in vivo infection model, multiple orthogonal methods\",\n      \"pmids\": [\"37870259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Proteomic analysis of primate hearts, SIRT2-deficient human pluripotent stem cell-derived cardiomyocytes, lentiviral SIRT2 overexpression in aged mice, acetylation assays\",\n      \"journal\": \"Nature aging\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — primate and human iPSC models, mechanistic axis (SIRT2-STAT3-CDKN2B) defined, in vivo rescue experiment, multiple orthogonal methods\",\n      \"pmids\": [\"37783815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP, chromatin immunoprecipitation, site-directed mutagenesis (S46A, S53A), BER reporter assay, oxidative stress treatment\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction shown, phosphorylation sites mapped, ChIP demonstrating OGG1 promoter binding, functional BER assay, multiple methods\",\n      \"pmids\": [\"38554113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro deacylation assay, fatty acylation detection, plasma membrane localization assay, Co-IP, cell migration assay\",\n      \"journal\": \"ChemMedChem / ACS chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic deacylation, site-specific mutagenesis, functional localization and effector recruitment shown, two independent studies\",\n      \"pmids\": [\"30734528\", \"31433161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SIRT2 and HDAC6 act synergistically to deacetylate cortactin, promoting bladder cancer cell migration and invasion. Cortactin is a substrate of SIRT2.\",\n      \"method\": \"siRNA knockdown, HDAC6 inhibitor (tubacin), migration and invasion assays\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional migration assay with siRNA, substrate identity implied but no direct deacetylation assay described in abstract\",\n      \"pmids\": [\"22089141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP, Western blot, siRNA knockdown, adenoviral overexpression, Sirt2 KO mouse model\",\n      \"journal\": \"Journal of the American Society of Nephrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — interaction shown by Co-IP, acetylation of MKP-1 detected, downstream signaling measured, but direct deacetylation site not defined in abstract\",\n      \"pmids\": [\"25349202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Overexpression, knockdown, chromatin immunoprecipitation, acetylation assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — ChIP showing reduced p65 promoter binding, deacetylation of p65 at K310 shown, functional rescue with miR-21 knockdown, single lab\",\n      \"pmids\": [\"24161395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP, deacetylation assay, SIRT2 overexpression/knockdown, proteasome inhibitor, lung cancer specimens\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct interaction by Co-IP, deacetylation-degradation link shown, functional p27 consequence, single lab\",\n      \"pmids\": [\"26942878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP, Western blot, immunohistochemistry, STZ diabetic rat model, SIRT2 overexpression in cardiomyocytes\",\n      \"journal\": \"European journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP interaction shown, α-tubulin deacetylation functional consequence demonstrated in disease model, single lab\",\n      \"pmids\": [\"26209361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP, mutation analysis (K294), GRE-reporter assay, overexpression/knockdown, LPS stimulation\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — site-specific mutagenesis at K294, GR translocation confirmed, functional cytokine reporter assay, single lab\",\n      \"pmids\": [\"32515550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP, site-directed mutagenesis, chaperone activity assay, apoptosis assay, mitophagy analysis\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct interaction and site-specific acetylation shown, functional chaperone alteration demonstrated, single lab\",\n      \"pmids\": [\"30352233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP, ubiquitination assay, actin polymerization assay, SIRT2 overexpression/knockdown\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct interaction shown by Co-IP, acetylation-ubiquitination coupling shown, functional actin/migration assay, single lab\",\n      \"pmids\": [\"29908203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ERK1/2 interacts with SIRT2 (exogenous and endogenous) and increases SIRT2 protein levels, stability, and deacetylase activity.\",\n      \"method\": \"Co-IP, deacetylase activity assay, MEK inhibitor (U0126), constitutively active MEK overexpression\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP, functional deacetylase activity regulation shown, single lab with two methods\",\n      \"pmids\": [\"23806683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"c-Src kinase interacts with and phosphorylates SIRT2 at Tyr104, modulating SIRT2 protein levels (decreasing them) and regulating SIRT2 deacetylase activity.\",\n      \"method\": \"Co-IP, site-directed mutagenesis, Src inhibitor (SU6656), siRNA knockdown of c-Src, deacetylase activity assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct interaction and phosphorylation site (Y104) identified, functional deacetylase activity effect shown, single lab\",\n      \"pmids\": [\"24996174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"I-SceI-based GFP HR reporter assay, siRNA depletion, RAD51 and RPA1 foci analysis\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — established epistasis in DSB repair by reporter assay and foci analysis, but mechanism of SIRT2 action (substrate not clearly defined) partially unclear\",\n      \"pmids\": [\"33624391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Site-directed mutagenesis, deacetylation assay on P38, siRNA, xenograft, pharmacological inhibitor (AK-7) resistance assay\",\n      \"journal\": \"Neoplasia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — SUMO site mapping with functional validation, new substrate (P38) identified, single lab\",\n      \"pmids\": [\"33316537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"SIRT2 knockout rat, metabolomics, adenoviral overexpression, immunoprecipitation, insulin secretion assay\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO rat with metabolic phenotype, deacetylation assay on GKRP, Co-IP for protein interaction, single lab\",\n      \"pmids\": [\"33754030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP, deacetylase-inactive mutant, knockdown/overexpression, xenograft metastasis model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP interaction, deacetylase activity requirement shown with catalytic mutant, in vivo metastasis assay, single lab\",\n      \"pmids\": [\"36344502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SIRT2 mediates PGAM5 deacetylation to activate malic enzyme 1 (ME1) activity (via ME1 dephosphorylation), promoting lipid synthesis and liver cancer cell proliferation.\",\n      \"method\": \"Immunoprecipitation, mass spectrometry, enzymatic activity assay, overexpression/knockdown\",\n      \"journal\": \"Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — MS identification, enzymatic activity assay, functional proliferation assay, single lab\",\n      \"pmids\": [\"37580952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SIRT2 deacetylates ACLY (ATP citrate lyase) in esophageal squamous cell carcinoma cells, promoting ACLY activity, lipid synthesis, and cancer cell proliferation and migration.\",\n      \"method\": \"Co-IP, AGK2 pharmacological inhibition, acetylation assay, overexpression rescue, xenograft model\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — interaction shown by Co-IP, acetylation change demonstrated, functional rescue, single lab\",\n      \"pmids\": [\"38426936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"TLR activation, autophagy flux analysis, extracellular deacetylation assay, site-specific acetylation detection in lung cancer patient serum\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — novel extracellular localization and activity shown, site-specific deacetylation demonstrated, patient sample correlation, single lab\",\n      \"pmids\": [\"36453571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP, SIRT2-specific inhibitor, deacetylation assay, overexpression/knockdown, in vivo embryo implantation assay\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP interaction, SIRT2 inhibitor functional test, in vivo mouse model, single lab\",\n      \"pmids\": [\"36418297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP, site-specific acetylation assay (K394), knockdown and pharmacological inhibition of SIRT2, LAP and phagocytosis assays, in vivo sepsis mouse model\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — site-specific deacetylation identified, functional downstream Atg4B-LC3-LAP pathway established, in vivo validation, single lab\",\n      \"pmids\": [\"36865524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP, nuclear fractionation, ChIP, overexpression in OPCs, neonatal hypoxia mouse model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — interaction and nuclear localization shown, genomic binding by ChIP demonstrated, functional rescue of OL maturation, single lab\",\n      \"pmids\": [\"35970992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Cardiomyocyte-specific Sirt2 knockout, Nrf2 double-knockout epistasis, NRF2 activity/protein level assays, cardiac functional measurements\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (Sirt2 KO x Nrf2 KO), NRF2 mechanistic link established, but molecular details of SIRT2-NRF2 interaction not fully specified in abstract\",\n      \"pmids\": [\"37728319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"RNA pulldown, QRE mutagenesis, mRNA half-life assay, QKI overexpression, qk viable mutant mouse\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct mRNA-protein interaction shown, transcript half-life measured, single lab\",\n      \"pmids\": [\"28188285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FBXO31, an F-box protein, interacts with SIRT2 and promotes proteasome-dependent degradation of SIRT2, binding to the sirtuin-type domain of SIRT2.\",\n      \"method\": \"Co-IP, protein half-life assay, ubiquitination assay, domain mapping, cancer cell xenograft\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP with domain mapping, ubiquitination and half-life assays, single lab\",\n      \"pmids\": [\"38216561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP, deacetylation activity assay, GARS mutation analysis, Drosophila genetic rescue model\",\n      \"journal\": \"Aging cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction and functional inhibition of SIRT2 activity shown, genetic epistasis in Drosophila model, multiple methods, single lab\",\n      \"pmids\": [\"34053152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"PROTAC degrader, pharmacological inhibitors (TM, AGK2), E-cadherin endocytosis assay, Sirt2 knockout mouse, IBD mouse model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway (Arf6-E-cadherin endocytosis) identified, PROTAC vs. inhibitor comparison reveals activity-specific mechanism, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"38648480\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SIRT2 is a predominantly cytoplasmic NAD+-dependent deacetylase (and defatty-acylase) that regulates diverse cellular processes—including mitosis (via CDH1/CDC20/APC-C and BubR1 deacetylation), glucose and lipid metabolism (PGAM2, PKM2, G6PD, IDH1, LKB1-AMPK, GKRP deacetylation), genome integrity (BRCA1-BARD1 heterodimerization, OGG1-dependent BER, HR), cytoskeletal dynamics (α-tubulin, cortactin), innate immunity (G3BP1/cGAS-STING, NF-κB/p65), cardiac homeostasis (NFATc2, STAT3, NRF2), and neurodegeneration (APP, AMPAR, α-tubulin)—through site-specific lysine deacetylation of a broad spectrum of substrates; its activity is regulated by post-translational modifications including ERK1/2-mediated stabilization, c-Src-mediated phosphorylation at Y104, ATM/ATR-mediated phosphorylation at S46/S53, SUMOylation at K183/K340, and S25 dephosphorylation by PPM1A/PPM1B that controls chromatin relocalization.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #5, #18]. 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 [#0, #2, #13]. 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 [#3, #5, #6, #10, #14, #15, #39]. 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 [#18, #25, #37]. 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 [#7, #8, #9, #20, #23, #24, #47]. 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 [#19, #26]. 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 [#11, #35, #36, #38].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP and gain/loss-of-function in 3T3-L1 adipocytes showing FOXO1 deacetylation and altered nuclear/cytosolic shuttling\",\n      \"pmids\": [\"17681146\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific lysine sites on FOXO1 not mapped\", \"Relationship between deacetylation and insulin-stimulated phosphorylation not fully resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined SIRT2's role in mitotic fidelity by showing it deacetylates APC/C coactivators, establishing a tumor-suppressor function against aneuploidy.\",\n      \"evidence\": \"Mouse knockout with deacetylation assays and mitotic phenotyping of CDH1/CDC20\",\n      \"pmids\": [\"22014574\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Acetylation sites on CDH1/CDC20 not specified\", \"Direct effect on APC/C catalytic activity inferred from substrate levels\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected SIRT2 to NF-κB transcriptional output and microtubule biology, broadening its substrate range to signaling and cytoskeletal targets.\",\n      \"evidence\": \"ChIP and acetylation assays for p65-K310/miR-21 in glioma; siRNA and confocal microscopy for α-tubulin/H4K16 in oocytes\",\n      \"pmids\": [\"24161395\", \"24334550\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tissue-specificity of p65 regulation unclear\", \"Direct vs indirect effects on tubulin acetylation not fully separated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"24786789\", \"24681946\", \"23806683\", \"24996174\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Integration of opposing ERK and Src inputs on a single SIRT2 pool unresolved\", \"Physiological stimuli controlling these PTMs not fully defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linked SIRT2-mediated BubR1 deacetylation to organismal lifespan, establishing the NAD+-SIRT2-BubR1 axis as an aging-relevant node.\",\n      \"evidence\": \"In vivo overexpression and NMN treatment with site-specific acetylation mapping and lifespan measurement in BubR1 hypomorphic mice\",\n      \"pmids\": [\"24825348\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether BubR1 stabilization fully accounts for lifespan effects unclear\", \"CBP/SIRT2 competition kinetics not quantified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Cemented SIRT2 as a master regulator of glycolytic flux by showing it controls enzyme oligomerization and activity (PKM2, G6PD), reprogramming cancer metabolism.\",\n      \"evidence\": \"Mass spectrometry site mapping, tetramerization and enzymatic activity assays, metabolic flux analysis, and xenograft models\",\n      \"pmids\": [\"27197174\", \"27586085\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Context-dependence across tumor types not delineated\", \"Net metabolic output integrating multiple enzyme targets not modeled\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended SIRT2 function into cardiac protection, synaptic plasticity, and oligodendrocyte biology, showing deacetylation of LKB1, AMPARs, and regulation of myelination programs.\",\n      \"evidence\": \"Knockout mice, site-specific deacetylation/ubiquitination assays, electrophysiology and behavior; RNA pulldown for QKI-mediated Sirt2 mRNA stabilization\",\n      \"pmids\": [\"28947430\", \"28793258\", \"28188285\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cross-talk between metabolic and trafficking substrates in single cell types unresolved\", \"How tissue-specific substrate selection is achieved unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved a spatial-regulation mechanism—S25 dephosphorylation by PPM1A/PPM1B drives SIRT2 chromatin relocalization—and expanded metabolic and hypertrophy roles (GKRP, NFATc2).\",\n      \"evidence\": \"Phosphoproteomics with S25 mutagenesis and subcellular fractionation during Listeria infection; Co-IP, glucose tolerance tests, and KO mouse hypertrophy models\",\n      \"pmids\": [\"29694890\", \"29296001\", \"29440391\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals coupling infection to phosphatase activation incompletely defined\", \"Genome-wide chromatin targets of relocalized SIRT2 not catalogued\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified SIRT2 as a defatty-acylase, revealing a non-deacetylase enzymatic activity that controls Ras-family GTPase membrane targeting.\",\n      \"evidence\": \"In vitro deacylation assays with site-specific mutagenesis and membrane localization/effector recruitment assays for K-Ras4a and RalB\",\n      \"pmids\": [\"30734528\", \"31433161\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative cellular contribution of deacylase vs deacetylase activity unquantified\", \"Acyl-substrate spectrum incompletely mapped\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established SIRT2 as an immunometabolic brake and uncovered SUMOylation as a determinant of its tumor-suppressor substrate selection.\",\n      \"evidence\": \"Sirt2 KO T-cell metabolomics and Seahorse flux; SUMO-site mutagenesis with p38 deacetylation assays and xenografts; IDH1-K224 deacetylation studies\",\n      \"pmids\": [\"32768387\", \"33316537\", \"32141187\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which SUMOylation redirects substrate choice unclear\", \"In vivo immunometabolic targets in human T cells not fully defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined SIRT2's direct role in DNA repair through BRCA1-BARD1 heterodimerization and HR/RAD51 recruitment, integrating it into genome-stability machinery.\",\n      \"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\",\n      \"pmids\": [\"33789098\", \"33624391\", \"34053152\", \"34642310\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HR roles depend on catalytic activity for all targets unclear\", \"Coordination of repair and mitotic functions of the same pool unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed SIRT2 controls APP processing and TGF-β/SMAD signaling via deacetylation-coupled ubiquitination, linking it to neurodegeneration and fibrosis.\",\n      \"evidence\": \"Site-specific deacetylation with APP/PS1 behavioral rescue; SMAD2/3 deacetylation with SMURF2 ubiquitination assays and renal KO models\",\n      \"pmids\": [\"35830807\", \"37777567\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether deacetylation directly primes ubiquitination or acts indirectly not fully resolved\", \"Neuronal vs systemic contributions to cognitive rescue not separated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined SIRT2 as a negative regulator of cGAS-STING innate immunity and a controller of cardiac aging via STAT3-CDKN2B and NRF2 axes.\",\n      \"evidence\": \"Site-specific G3BP1 deacetylation with cGAS activity assays and HSV-1 infection; proteomics and SIRT2-deficient iPSC-cardiomyocytes; cardiomyocyte Sirt2 x Nrf2 epistasis\",\n      \"pmids\": [\"37870259\", \"37783815\", \"37728319\", \"36786216\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular nature of SIRT2-NRF2 regulation not specified\", \"Balance between protective and detrimental cardiac roles context-dependent\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"evidence\": \"ChIP and S46/S53 mutagenesis for OGG1-dependent BER; PROTAC degrader vs AGK2 inhibitor in IBD model targeting Arf6-E-cadherin endocytosis\",\n      \"pmids\": [\"38554113\", \"38648480\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Catalytic-independent scaffolding functions not systematically mapped\", \"Distinct in vivo consequences of inhibition vs degradation not generalized across tissues\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 3, 5, 6, 7, 8, 10, 14, 18, 20, 21, 22, 23, 26]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 5, 19, 26]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 5, 6, 8, 14, 17, 21]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [11, 46]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [11, 25, 46]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [18, 46]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [12, 31]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [43]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 2, 13]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [3, 5, 6, 10, 14, 15, 39]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [18, 25, 37]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [15, 23]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 9, 21, 24]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [17, 21, 30, 49]}\n    ],\n    \"complexes\": [\"BRCA1-BARD1\"],\n    \"partners\": [\"BRCA1\", \"BARD1\", \"OGG1\", \"G3BP1\", \"LKB1\", \"NFATc2\", \"FOXO1\", \"HIF1A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}