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NAD-dependent protein deacetylase sirtuin-2



Mus musculus (Mouse)
Reviewed-Annotation score: -Experimental evidence at protein leveli


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:17521387, PubMed:17681146, PubMed:17574768, PubMed:19037106, PubMed:22014574, PubMed:21791548, PubMed:21841822, PubMed:24334550). 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. Plays a major role in the control of cell cycle progression and genomic stability. Functions in the antephase checkpoint preventing precocious mitotic entry in response to microtubule stress agents, and hence allowing proper inheritance of chromosomes. Positively regulates the anaphase promoting complex/cyclosome (APC/C) ubiquitin ligase complex activity by deacetylating CDC20 and FZR1, then allowing progression through mitosis. Associates both with chromatin at transcriptional start sites (TSSs) and enhancers of active genes. 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. 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. Deacetylates KMT5A modulating KMT5A chromatin localization during the mitotic stress response. Deacetylates also histone H3 at 'Lys-57' (H3K56ac) during the mitotic G2/M transition. 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. Deacetylates histone H4 at 'Lys-16' (H4K16ac) at the VEGFA promoter and thereby contributes to regulate expression of VEGFA, a key regulator of angiogenesis. Deacetylates alpha-tubulin at 'Lys-40' and hence controls neuronal motility, oligodendroglial cell arbor projection processes and proliferation of non-neuronal cells. 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. Deacetylates PARD3 and participates in the regulation of Schwann cell peripheral myelination formation during early postnatal development and during postinjury remyelination. Involved in several cellular metabolic pathways. Plays a role in the regulation of blood glucose homeostasis by deacetylating and stabilizing phosphoenolpyruvate carboxykinase PCK1 activity in response to low nutrient availability. 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. Maintains energy homeostasis in response to nutrient deprivation as well as energy expenditure by inhibiting adipogenesis and promoting lipolysis. Attenuates adipocyte differentiation by deacetylating and promoting FOXO1 interaction to PPARG and subsequent repression of PPARG-dependent transcriptional activity. Plays a role in the regulation of lysosome-mediated degradation of protein aggregates by autophagy in neuronal cells. Deacetylates FOXO1 in response to oxidative stress or serum deprivation, thereby negatively regulating FOXO1-mediated autophagy (By similarity). 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. Deacetylates RELA in the cytoplasm inhibiting NF-kappaB-dependent transcription activation upon TNF-alpha stimulation. Inhibits transcriptional activation by deacetylating p53/TP53 and EP300. Deacetylates also EIF5A. Functions as a negative regulator on oxidative stress-tolerance in response to anoxia-reoxygenation conditions. Plays a role as tumor suppressor (PubMed:22014574, PubMed:23468428).By similarity10 Publications
Isoform 1: Deacetylates alpha-tubulin.
Isoform 2: Deacetylates alpha-tubulin.
Isoform 4: Deacetylates alpha-tubulin.

Catalytic activityi

NAD+ + an acetylprotein = nicotinamide + O-acetyl-ADP-ribose + a protein.PROSITE-ProRule annotation


Zn2+By similarityNote: Binds 1 zinc ion per subunit.By similarity

Enzyme regulationi

Inhibited by Sirtinol, A3 and M15 small molecules. Inhibited by nicotinamide. Inhibited by a macrocyclic peptide inhibitor S2iL5. Inhibited by EP300-induced acetylation (By similarity).By similarity


Feature keyPosition(s)DescriptionActionsGraphical viewLength
Active sitei187Proton acceptorPROSITE-ProRule annotation1
Metal bindingi195ZincPROSITE-ProRule annotation1
Metal bindingi200ZincPROSITE-ProRule annotation1
Metal bindingi221ZincPROSITE-ProRule annotation1
Metal bindingi224ZincPROSITE-ProRule annotation1
Binding sitei324NAD; via amide nitrogenBy similarity1


Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi85 – 89NADBy similarity5
Nucleotide bindingi95 – 97NADBy similarity3
Nucleotide bindingi167 – 170NADBy similarity4
Nucleotide bindingi262 – 263NADBy similarity2
Nucleotide bindingi286 – 288NADBy similarity3

GO - Molecular functioni

  • chromatin binding Source: UniProtKB
  • histone acetyltransferase binding Source: UniProtKB
  • histone deacetylase activity Source: UniProtKB
  • histone deacetylase binding Source: UniProtKB
  • NAD+ binding Source: MGI
  • NAD-dependent histone deacetylase activity Source: UniProtKB
  • NAD-dependent histone deacetylase activity (H4-K16 specific) Source: UniProtKB
  • NAD-dependent protein deacetylase activity Source: UniProtKB
  • protein deacetylase activity Source: UniProtKB
  • transcription factor binding Source: UniProtKB
  • tubulin deacetylase activity Source: UniProtKB
  • ubiquitin binding Source: UniProtKB
  • zinc ion binding Source: MGI

GO - Biological processi

  • autophagy Source: UniProtKB-KW
  • cell division Source: UniProtKB-KW
  • cellular lipid catabolic process Source: UniProtKB
  • cellular response to caloric restriction Source: UniProtKB
  • cellular response to epinephrine stimulus Source: UniProtKB
  • cellular response to hepatocyte growth factor stimulus Source: UniProtKB
  • cellular response to hypoxia Source: UniProtKB
  • cellular response to molecule of bacterial origin Source: UniProtKB
  • cellular response to oxidative stress Source: UniProtKB
  • hepatocyte growth factor receptor signaling pathway Source: UniProtKB
  • histone deacetylation Source: MGI
  • histone H3 deacetylation Source: UniProtKB
  • histone H4 deacetylation Source: UniProtKB
  • meiotic cell cycle Source: UniProtKB-KW
  • myelination in peripheral nervous system Source: UniProtKB
  • negative regulation of autophagy Source: UniProtKB
  • negative regulation of cell proliferation Source: UniProtKB
  • negative regulation of defense response to bacterium Source: UniProtKB
  • negative regulation of fat cell differentiation Source: UniProtKB
  • negative regulation of NLRP3 inflammasome complex assembly Source: MGI
  • negative regulation of oligodendrocyte progenitor proliferation Source: UniProtKB
  • negative regulation of peptidyl-threonine phosphorylation Source: UniProtKB
  • negative regulation of protein catabolic process Source: UniProtKB
  • negative regulation of reactive oxygen species metabolic process Source: UniProtKB
  • negative regulation of striated muscle tissue development Source: UniProtKB
  • negative regulation of transcription, DNA-templated Source: UniProtKB
  • negative regulation of transcription by RNA polymerase II Source: UniProtKB
  • negative regulation of transcription from RNA polymerase II promoter in response to hypoxia Source: UniProtKB
  • peptidyl-lysine deacetylation Source: UniProtKB
  • phosphatidylinositol 3-kinase signaling Source: UniProtKB
  • positive regulation of attachment of spindle microtubules to kinetochore Source: UniProtKB
  • positive regulation of cell division Source: UniProtKB
  • positive regulation of DNA binding Source: UniProtKB
  • positive regulation of execution phase of apoptosis Source: UniProtKB
  • positive regulation of meiotic nuclear division Source: UniProtKB
  • positive regulation of oocyte maturation Source: UniProtKB
  • positive regulation of proteasomal ubiquitin-dependent protein catabolic process Source: UniProtKB
  • positive regulation of proteasomal ubiquitin-dependent protein catabolic process involved in cellular response to hypoxia Source: UniProtKB
  • positive regulation of transcription by RNA polymerase II Source: UniProtKB
  • proteasome-mediated ubiquitin-dependent protein catabolic process Source: UniProtKB
  • protein deacetylation Source: UniProtKB
  • protein kinase B signaling Source: UniProtKB
  • regulation of cell cycle Source: UniProtKB
  • regulation of fat cell differentiation Source: MGI
  • regulation of myelination Source: UniProtKB
  • transcription, DNA-templated Source: UniProtKB-KW
  • tubulin deacetylation Source: UniProtKB


Molecular functionHydrolase
Biological processAutophagy, Cell cycle, Cell division, Differentiation, Meiosis, Mitosis, Neurogenesis, Transcription, Transcription regulation
LigandMetal-binding, NAD, Zinc

Names & Taxonomyi

Protein namesi
Recommended name:
NAD-dependent protein deacetylase sirtuin-2 (EC:3.5.1.-)
Alternative name(s):
Regulatory protein SIR2 homolog 2
SIR2-like protein 2
Short name:
Gene namesi
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
  • UP000000589 Componenti: Chromosome 7

Organism-specific databases

MGIiMGI:1927664. Sirt2.

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cell membrane, Cell projection, Chromosome, Cytoplasm, Cytoskeleton, Membrane, Microtubule, Nucleus

Pathology & Biotechi

Disruption phenotypei

Tissue-specific knockout of SIRT2 in Schwann cells of early postnatal mice leads to a transient delay in myelination, a reduction in the nerve conduction velocity and hyperacetylation of PARD3. The number of dividing Schwann cells in the developing nerve and alpha-tubulin acetylation are normal (PubMed:21949390). Mutant mice embryo grow normally and new born are healthy. Embryonic fibroblasts (MEFs) display reduced cell proliferation capacity, centrosome amplification and mitotic cell death. Nude mice inoculated with immortalized MEFs from mutant mice developed tumors. Adult mutant mice exhibit genomic instability and chromosomal aberrations, such as double-strand breaks (DSBs), with a gender-specific spectrum of tumorigenesis; females develop primarily mammary tumors and males develop tumors in several organs, including the liver, lung, pancreas, stomach, duodenum and prostate. Drastic increases of histone H4K16 acetylation and decreases of both histone methylation (H4K20me1) in metaphasic chromosomes and histone methylations (H4K20me2/3) in late M/early G1 but also throughout all phases of the cell cycle (PubMed:23468428).3 Publications


Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi187H → A: Abolishes deacetylation of FOXO3. Does not inhibit interaction with FOXO3. 2 Publications1

Chemistry databases


PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemovedBy similarity
ChainiPRO_00001102592 – 389NAD-dependent protein deacetylase sirtuin-2Add BLAST388

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei2N-acetylalanineBy similarity1
Modified residuei23PhosphoserineCombined sources1
Modified residuei25PhosphoserineCombined sources1
Modified residuei27PhosphothreonineCombined sources1
Modified residuei53PhosphoserineBy similarity1
Modified residuei100PhosphoserineBy similarity1
Modified residuei368PhosphoserineCombined sources1
Modified residuei372PhosphoserineCombined sources1

Post-translational modificationi

Phosphorylated at phosphoserine and phosphothreonine. Phosphorylated at Ser-368 by a mitotic kinase CDK1/cyclin B at the G2/M transition; phosphorylation regulates the delay in cell-cycle progression. Phosphorylated at Ser-368 by a mitotic kinase G1/S-specific cyclin E/Cdk2 complex; phosphorylation inactivates SIRT2-mediated alpha-tubulin deacetylation and thereby negatively regulates cell adhesion, cell migration and neurite outgrowth during neuronal differentiation. Phosphorylated by cyclin A/Cdk2 and p35-Cdk5 complexes and to a lesser extent by the cyclin D3/Cdk4 and cyclin B/Cdk1, in vitro. Dephosphorylated at Ser-368 by CDC14A and CDC14B around early anaphase (By similarity).By similarity
Acetylated by EP300; acetylation leads both to the decreased of SIRT2-mediated alpha-tubulin deacetylase activity and SIRT2-mediated down-regulation of TP53 transcriptional activity.By similarity
Ubiquitinated.By similarity

Keywords - PTMi

Acetylation, Phosphoprotein, Ubl conjugation

Proteomic databases


PTM databases



Tissue specificityi

Isoform 1 is weakly expressed in the cortex at postnatal(P) days P1, P3 and P7, and increases progressively between P17 and older adult cortex. Isoform 1 is also expressed in heart, liver and skeletal muscle, weakly expressed in the striatum and spinal cord. Isoform 2 is not expressed in the cortex at P1, P3 and P7, and increases strongly and progressively between P17 and older adult cortex. Isoform 2 is also expressed in the heart, liver, striatum and spinal cord. Isoform 4 is weakly expressed in older adult cortex and spinal cords. Expressed in the cortex. Expressed in postnatal sciatic nerves during myelination and during remyelination after nerve injury. Expressed in neurons, oligodendrocytes, Schwann cells, Purkinje cells and in astrocytes of white matter. Strongly expressed in preadipocytes compared with differentiated adipocytes. Expressed in cerebellar granule cells. Expressed in the inner ear: in the cochlea, expressed in types I and V fibrocytes in the spiral ligament (SL) and slightly in stria vascularis (SV); in the organ of Corti, expressed in some supporting cells; in the crista ampullaris, expressed in spiral ganglion cells; also expressed in the endolymphatic sac (ES) epithelial cells (at protein level). Expressed in the brain, spinal cord, optic nerve and hippocampus. Strongly expressed in 6-8 week-old ovulated meiosis II oocytes and weakly expressed in 45-58 week-old ovulated meiosis II oocytes. Expressed in the cochlea, vestibule and acoustic nerve of the inner ear.8 Publications

Developmental stagei

Isoform 1 is expressed in the cortex at 15.5 dpc. Isoform 2 is not detected in the cortex at 15.5 dpc (at protein level).


Up-regulated in response to caloric restriction in white and brown adipose tissues. Up-regulated during cold exposure and down-regulated in higher ambient temperature in brown adipose tissue. Up-regulated after beta-adrenergic agonist (isoproterenol) treatment in white adipose tissue (at protein level). Up-regulated in response to caloric restriction in adipose tissue and kidney. Up-regulated in response to oxidative stress. Up-regulated during postnatal sciatic nerve myelination development and axonal regeneration. Down-regulated during preadipocyte differentiation. Down-regulated in Schwann dedifferentiated cells during Wallerian degeneration. Isoform 1 is up-regulated upon differentiation to a neuron-like phenotype.5 Publications

Gene expression databases

ExpressionAtlasiQ8VDQ8. baseline and differential.
GenevisibleiQ8VDQ8. MM.


Subunit structurei

Interacts with CDC20, FOXO3 and FZR1 (PubMed:17521387, PubMed:22014574). Associates with microtubule in primary cortical mature neurons (By similarity). Homotrimer. Interacts (via both phosphorylated, unphosphorylated, active or inactive forms) with HDAC6; the interaction is necessary for the complex to interact with alpha-tubulin, suggesting that these proteins belong to a large complex that deacetylates the cytoskeleton. Interacts with FOXO1; the interaction is disrupted upon serum-starvation or oxidative stress, leading to increased level of acetylated FOXO1 and induction of autophagy (PubMed:17681146, PubMed:19037106). Interacts with RELA; the interaction occurs in the cytoplasm and is increased in a TNF-alpha-dependent manner. Interacts with HOXA10; the interaction is direct. Interacts with YWHAB and YWHAG; the interactions occur in a AKT-dependent manner and increase SIRT2-dependent TP53 deacetylation. Interacts with MAPK1/ERK2 and MAPK3/ERK1; the interactions increase SIRT2 stability and deacetylation activity. Interacts (phosphorylated form) with KMT5A isoform 2; the interaction is direct, stimulates KMT5A-mediated methyltransferase activity on histone at 'Lys-20' (H4K20me1) and is increased in a H2O2-induced oxidative stress-dependent manner. Interacts with G6PD; the interaction is enhanced by H2O2 treatment. Interacts with a G1/S-specific cyclin E-CDK2 complex. Interacts with AURKA, CDK5R1 (p35 form) and CDK5 and HIF1A. Interacts with the tRNA ligase SARS; recruited to the VEGFA promoter via interaction with SARS (By similarity). Isoform 2 and isoform 4 associate with microtubules in primary cortical mature neurons. Interacts with BEX4; negatively regulates alpha-tubulin deacetylation by SIRT2 (By similarity).By similarity5 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

Protein-protein interaction databases

BioGridi211070. 23 interactors.
IntActiQ8VDQ8. 13 interactors.


3D structure databases


Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini65 – 340Deacetylase sirtuin-typePROSITE-ProRule annotationAdd BLAST276


Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni116 – 120Peptide inhibitor bindingBy similarity5
Regioni232 – 301Peptide inhibitor bindingBy similarityAdd BLAST70


Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi41 – 51Nuclear export signalBy similarityAdd BLAST11

Sequence similaritiesi

Belongs to the sirtuin family. Class I subfamily.Curated

Phylogenomic databases

eggNOGiKOG2682. Eukaryota.
COG0846. LUCA.

Family and domain databases

Gene3Di3.30.1600.10. 2 hits.
InterProiView protein in InterPro
IPR029035. DHS-like_NAD/FAD-binding_dom.
IPR003000. Sirtuin.
IPR026591. Sirtuin_cat_small_dom_sf.
IPR017328. Sirtuin_class_I.
IPR026590. Ssirtuin_cat_dom.
PfamiView protein in Pfam
PF02146. SIR2. 1 hit.
PIRSFiPIRSF037938. SIR2_euk. 1 hit.
SUPFAMiSSF52467. SSF52467. 1 hit.
PROSITEiView protein in PROSITE
PS50305. SIRTUIN. 1 hit.

Sequences (4)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 4 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q8VDQ8-1) [UniParc]FASTAAdd to basket
Also known as: SIRT2.1

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

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        10         20         30         40         50
60 70 80 90 100
110 120 130 140 150
160 170 180 190 200
210 220 230 240 250
260 270 280 290 300
310 320 330 340 350
360 370 380
Mass (Da):43,256
Last modified:October 31, 2003 - v2
Isoform 2 (identifier: Q8VDQ8-2) [UniParc]FASTAAdd to basket
Also known as: SIRT2.2

The sequence of this isoform differs from the canonical sequence as follows:
     1-37: Missing.

Show »
Mass (Da):39,554
Isoform 3 (identifier: Q8VDQ8-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     236-389: Missing.

Show »
Mass (Da):26,518
Isoform 4 (identifier: Q8VDQ8-4) [UniParc]FASTAAdd to basket
Also known as: SIRT2.3

The sequence of this isoform differs from the canonical sequence as follows:

Note: Gene prediction based on EST data.
Show »
Mass (Da):35,678

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti230P → L in AAG32038 (PubMed:11056054).Curated1
Sequence conflicti241S → P in AAH21439 (PubMed:15489334).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0087291 – 37Missing in isoform 2. 1 PublicationAdd BLAST37
Alternative sequenceiVSP_0553296 – 76PSDPL…QSERC → R in isoform 4. CuratedAdd BLAST71
Alternative sequenceiVSP_055330236 – 389Missing in isoform 3. 1 PublicationAdd BLAST154

Sequence databases

Select the link destinations:
Links Updated
AF299337 mRNA. Translation: AAG39256.1.
, AF302265, AF302266, AF302267, AF302268, AF302269, AF302270, AF302271 Genomic DNA. Translation: AAG32038.1.
AK014042 mRNA. Translation: BAB29128.1.
KF032392 mRNA. Translation: AGZ02590.1.
AC171210 Genomic DNA. No translation available.
BC021439 mRNA. Translation: AAH21439.1.
CCDSiCCDS21055.1. [Q8VDQ8-1]
CCDS52165.1. [Q8VDQ8-4]
CCDS85253.1. [Q8VDQ8-2]
RefSeqiNP_001116237.1. NM_001122765.1. [Q8VDQ8-2]
NP_001116238.1. NM_001122766.1. [Q8VDQ8-4]
NP_071877.3. NM_022432.4. [Q8VDQ8-1]

Genome annotation databases

EnsembliENSMUST00000072965; ENSMUSP00000072732; ENSMUSG00000015149. [Q8VDQ8-1]
ENSMUST00000122915; ENSMUSP00000147217; ENSMUSG00000015149. [Q8VDQ8-2]
ENSMUST00000170068; ENSMUSP00000132783; ENSMUSG00000015149. [Q8VDQ8-4]
UCSCiuc009fzt.2. mouse. [Q8VDQ8-1]
uc012fgx.1. mouse. [Q8VDQ8-4]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Entry informationi

Entry nameiSIR2_MOUSE
AccessioniPrimary (citable) accession number: Q8VDQ8
Secondary accession number(s): E9PXF5
, Q9CXS5, Q9EQ18, Q9ERJ9, U5TP50
Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 31, 2003
Last sequence update: October 31, 2003
Last modified: March 28, 2018
This is version 162 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program


Keywords - Technical termi

Complete proteome, Direct protein sequencing, Reference proteome