Protein: NAD-dependent protein deacetylase sirtuin-2 (EC 2.3.1.286) (NAD-dependent protein defatty-acylase sirtuin-2) (EC 2.3.1.-) (Regulatory protein SIR2 homolog 2) (SIR2-like protein 2) (Q5RJQ4)
Organism: Rattus norvegicus (Rat)
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. 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. 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 (By similarity).
Subcellular location: Nucleus {ECO:0000250|UniProtKB:Q8IXJ6}. Cytoplasm, perinuclear region {ECO:0000250|UniProtKB:Q8VDQ8}. Cytoplasm {ECO:0000269|PubMed:17344398}. Cytoplasm, cytoskeleton {ECO:0000250|UniProtKB:Q8IXJ6}. Cytoplasm, cytoskeleton, microtubule organizing center, centrosome {ECO:0000250|UniProtKB:Q8IXJ6}. Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriole {ECO:0000250|UniProtKB:Q8IXJ6}. Cytoplasm, cytoskeleton, spindle {ECO:0000250|UniProtKB:Q8IXJ6}. Midbody {ECO:0000250|UniProtKB:Q8IXJ6}. Chromosome {ECO:0000250|UniProtKB:Q8IXJ6}. Perikaryon {ECO:0000269|PubMed:17344398}. Cell projection {ECO:0000250|UniProtKB:Q8VDQ8}. Cell projection, growth cone {ECO:0000250|UniProtKB:Q8VDQ8}. Myelin membrane {ECO:0000269|PubMed:17344398}. Note=Localizes in the cytoplasm during most of the cell cycle except in the G2/M transition and during mitosis, where it is localized in association with chromatin and induces deacetylation of histone at 'Lys-16' (H4K16ac). Colocalizes with KMT5A at mitotic foci. Colocalizes with CDK1 at centrosome during prophase and splindle fibers during metaphase. Colocalizes with Aurora kinase AURKA at centrosome during early prophase and in the centrioles and growing mitotic spindle throughout metaphase. Colocalizes with Aurora kinase AURKB during cytokinesis with the midbody. Colocalizes with microtubules (By similarity). Detected in perinuclear foci that may be aggresomes containing misfolded, ubiquitinated proteins (By similarity). Shuttles between the cytoplasm and the nucleus through the CRM1 export pathway. Colocalizes with EP300 in the nucleus. Translocates to the nucleus and chromatin upon bacterium Listeria monocytogenes infection in interphase cells (By similarity). Deacetylates FOXO3 in the cytoplasm. Colocalizes with PLP1 in internodal regions, at paranodal axoglial junction and Schmidt-Lanterman incisures of myelin sheat. Colocalizes with CDK5R1 in the perikaryon, neurites and growth cone of hippocampal neurons. Colocalizes with alpha-tubulin in neuronal growth cone. Localizes in the cytoplasm and nucleus of germinal vesicle (GV) stage oocytes. Colocalizes with alpha-tubulin on the meiotic spindle as the oocytes enter into metaphase, and also during meiotic anaphase and telophase, especially with the midbody. Colocalizes with PARD3 in internodal region of axons (By similarity). Colocalizes with acetylated alpha-tubulin in cell projection processes during primary oligodendrocyte precursor (OLP) differentiation (By similarity). {ECO:0000250|UniProtKB:Q8IXJ6, ECO:0000250|UniProtKB:Q8VDQ8}.
Sequence: MDFLRNLFTQTLGLGSQKERLLDELTLEGVTRYMQSERCRRVICLVGAGISTSAGIPDFRSPSTGLYANLEKYHLPYPEAIFEISYFKKHPEPFFALAKELYPGQFKPTICHYFIRLLKEKGLLLRCYTQNIDTLERVAGLEPQDLVEAHGTFYTSHCVNTSCGKEYTMSWMKEKIFSEATPKCEKCQNVVKPDIVFFGENLPPRFFSCMQSDFSKVDLLIIMGTSLQVQPFASLISKAPLATPRLLINKEKTGQTDPFLGMMMGLGGGMDFDSKKAYRDVAWLGDCDQGCLALADLLGWKELEDLVRREHANIDAQSGSQASNPSATVSPRKSPPPAKEAARTKEKEEH
InterPro domains: - IPR050134: NAD-dependent sirtuin protein deacylases (family) [20-307]
- IPR029035: DHS-like NAD/FAD-binding domain superfamily (homologous_superfamily) [22-308]
- IPR003000: Sirtuin family (family) [47-231]
- IPR017328: Sirtuin, class I (family) [8-350]
- IPR026591: Sirtuin, catalytic core small domain superfamily (homologous_superfamily) [53-203]
- IPR026590: Sirtuin family, catalytic core domain (domain) [20-301]
Interaction partners: - NAD-dependent protein lipoamidase sirtuin-4, mitochondrial
- NAD-dependent protein deacylase sirtuin-5, mitochondrial
- Sirtuin 6 6
- Nicotinamide phosphoribosyltransferase
- NAD-dependent protein deacetylase sirtuin-1
- NAD-dependent protein deacetylase sirtuin-7
- NAD-dependent protein deacetylase
- Nicotinamide-nucleotide adenylyltransferase
- Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 2
- Glutamine-dependent NAD
Gene Ontology annotations:
Molecular Function (MF): GO:0003674 (molecular function), GO:0005488 (binding), GO:0005515 (protein binding), GO:0019899 (enzyme binding)
Biological Process (BP): GO:0008150 (biological process), GO:0048518 (positive regulation of biological process), GO:0050789 (regulation of biological process), GO:0065007 (biological regulation), GO:0050896 (response to stimulus), GO:0009987 (cellular process), GO:0008152 (metabolic process), GO:0048519 (negative regulation of biological process), GO:0042221 (response to chemical), GO:0006807 (nitrogen compound metabolic process), GO:0009892 (negative regulation of metabolic process), GO:0065008 (regulation of biological quality), GO:0009719 (response to endogenous stimulus), GO:0050794 (regulation of cellular process), GO:0051716 (cellular response to stimulus), GO:0048523 (negative regulation of cellular process), GO:0009058 (biosynthetic process), GO:0019222 (regulation of metabolic process), GO:0071704 (organic substance metabolic process), GO:0009056 (catabolic process), GO:0044237 (cellular metabolic process), GO:0009893 (positive regulation of metabolic process), GO:0044238 (primary metabolic process), GO:0048522 (positive regulation of cellular process), GO:0001101 (response to acid chemical), GO:0010942 (positive regulation of cell death), GO:0060548 (negative regulation of cell death), GO:0044248 (cellular catabolic process), GO:0071495 (cellular response to endogenous stimulus), GO:0060255 (regulation of macromolecule metabolic process), GO:0006725 (cellular aromatic compound metabolic process), GO:0009894 (regulation of catabolic process), GO:1901360 (organic cyclic compound metabolic process), GO:0010605 (negative regulation of macromolecule metabolic process), GO:0051171 (regulation of nitrogen compound metabolic process), GO:1901575 (organic substance catabolic process), GO:0051128 (regulation of cellular component organization), GO:0044260 (cellular macromolecule metabolic process), GO:0051173 (positive regulation of nitrogen compound metabolic process), GO:0051172 (negative regulation of nitrogen compound metabolic process), GO:1901564 (organonitrogen compound metabolic process), GO:1901576 (organic substance biosynthetic process), GO:0010604 (positive regulation of macromolecule metabolic process), GO:0046483 (heterocycle metabolic process), GO:0019538 (protein metabolic process), GO:0044249 (cellular biosynthetic process), GO:1901700 (response to oxygen-containing compound), GO:0034641 (cellular nitrogen compound metabolic process), GO:0031647 (regulation of protein stability), GO:0031324 (negative regulation of cellular metabolic process), GO:0043170 (macromolecule metabolic process), GO:0010033 (response to organic substance), GO:0009891 (positive regulation of biosynthetic process), GO:0009991 (response to extracellular stimulus), GO:0010941 (regulation of cell death), GO:0007584 (response to nutrient), GO:1901698 (response to nitrogen compound), GO:0006139 (nucleobase-containing compound metabolic process), GO:0031325 (positive regulation of cellular metabolic process), GO:0070887 (cellular response to chemical stimulus), GO:0009889 (regulation of biosynthetic process), GO:0031323 (regulation of cellular metabolic process), GO:0009890 (negative regulation of biosynthetic process), GO:0080090 (regulation of primary metabolic process), GO:0009896 (positive regulation of catabolic process), GO:0009059 (macromolecule biosynthetic process), GO:0044270 (cellular nitrogen compound catabolic process), GO:0010556 (regulation of macromolecule biosynthetic process), GO:0051246 (regulation of protein metabolic process), GO:0043069 (negative regulation of programmed cell death), GO:0043067 (regulation of programmed cell death), GO:2000378 (negative regulation of reactive oxygen species metabolic process), GO:0030163 (protein catabolic process), GO:0051881 (regulation of mitochondrial membrane potential), GO:0010468 (regulation of gene expression), GO:1901566 (organonitrogen compound biosynthetic process), GO:0009057 (macromolecule catabolic process), GO:0043412 (macromolecule modification), GO:0090304 (nucleic acid metabolic process), GO:0031667 (response to nutrient levels), GO:0018130 (heterocycle biosynthetic process), GO:1901361 (organic cyclic compound catabolic process), GO:0031327 (negative regulation of cellular biosynthetic process), GO:0051252 (regulation of RNA metabolic process), GO:1901701 (cellular response to oxygen-containing compound), GO:0045934 (negative regulation of nucleobase-containing compound metabolic process), GO:0071417 (cellular response to organonitrogen compound), GO:0043200 (response to amino acid), GO:0031344 (regulation of cell projection organization), GO:0042176 (regulation of protein catabolic process), GO:0071310 (cellular response to organic substance), GO:0043068 (positive regulation of programmed cell death), GO:0051248 (negative regulation of protein metabolic process), GO:1901699 (cellular response to nitrogen compound), GO:1901135 (carbohydrate derivative metabolic process), GO:0036211 (protein modification process), GO:0010557 (positive regulation of macromolecule biosynthetic process), GO:0045935 (positive regulation of nucleobase-containing compound metabolic process), GO:0051254 (positive regulation of RNA metabolic process), GO:0010243 (response to organonitrogen compound), GO:0044265 (cellular macromolecule catabolic process), GO:0031326 (regulation of cellular biosynthetic process), GO:0051247 (positive regulation of protein metabolic process), GO:0019219 (regulation of nucleobase-containing compound metabolic process), GO:0045732 (positive regulation of protein catabolic process), GO:0010558 (negative regulation of macromolecule biosynthetic process), GO:0044271 (cellular nitrogen compound biosynthetic process), GO:0031331 (positive regulation of cellular catabolic process), GO:0014070 (response to organic cyclic compound), GO:0031329 (regulation of cellular catabolic process), GO:0051253 (negative regulation of RNA metabolic process), GO:0031669 (cellular response to nutrient levels), GO:0031328 (positive regulation of cellular biosynthetic process), GO:0042981 (regulation of apoptotic process), GO:0030162 (regulation of proteolysis), GO:0031400 (negative regulation of protein modification process), GO:0098732 (macromolecule deacylation), GO:2001141 (regulation of RNA biosynthetic process), GO:0018193 (peptidyl-amino acid modification), GO:0035601 (protein deacylation), GO:2000112 (regulation of cellular macromolecule biosynthetic process), GO:1902680 (positive regulation of RNA biosynthetic process), GO:1902679 (negative regulation of RNA biosynthetic process), GO:0097306 (cellular response to alcohol), GO:2000058 (regulation of ubiquitin-dependent protein catabolic process), GO:0071870 (cellular response to catecholamine stimulus), GO:0016311 (dephosphorylation), GO:0043065 (positive regulation of apoptotic process), GO:0120035 (regulation of plasma membrane bounded cell projection organization), GO:0031399 (regulation of protein modification process), GO:0043066 (negative regulation of apoptotic process), GO:0014075 (response to amine), GO:0006355 (regulation of DNA-templated transcription), GO:0071407 (cellular response to organic cyclic compound), GO:0051603 (proteolysis involved in protein catabolic process), GO:0002791 (regulation of peptide secretion), GO:0045862 (positive regulation of proteolysis), GO:1901800 (positive regulation of proteasomal protein catabolic process), GO:2000060 (positive regulation of ubiquitin-dependent protein catabolic process), GO:0061136 (regulation of proteasomal protein catabolic process), GO:0045861 (negative regulation of proteolysis), GO:0032774 (RNA biosynthetic process), GO:0097659 (nucleic acid-templated transcription), GO:0070301 (cellular response to hydrogen peroxide), GO:0016570 (histone modification), GO:0070374 (positive regulation of ERK1 and ERK2 cascade), GO:0006476 (protein deacetylation), GO:0045892 (negative regulation of DNA-templated transcription), GO:1903508 (positive regulation of nucleic acid-templated transcription), GO:1903506 (regulation of nucleic acid-templated transcription), GO:0032436 (positive regulation of proteasomal ubiquitin-dependent protein catabolic process), GO:0010975 (regulation of neuron projection development), GO:0070372 (regulation of ERK1 and ERK2 cascade), GO:0006357 (regulation of transcription by RNA polymerase II), GO:0045893 (positive regulation of DNA-templated transcription), GO:1903320 (regulation of protein modification by small protein conjugation or removal), GO:1903052 (positive regulation of proteolysis involved in protein catabolic process), GO:0032434 (regulation of proteasomal ubiquitin-dependent protein catabolic process), GO:1903321 (negative regulation of protein modification by small protein conjugation or removal), GO:1903507 (negative regulation of nucleic acid-templated transcription), GO:0016575 (histone deacetylation), GO:0000122 (negative regulation of transcription by RNA polymerase II), GO:0010799 (regulation of peptidyl-threonine phosphorylation), GO:0031397 (negative regulation of protein ubiquitination), GO:0031396 (regulation of protein ubiquitination), GO:0070932 (histone H3 deacetylation), GO:0031397 (negative regulation of protein ubiquitination), GO:0031398 (positive regulation of protein ubiquitination)
Cellular Component (CC): GO:0005575 (cellular component), GO:0110165 (cellular anatomical entity), GO:0005622 (intracellular anatomical structure), GO:0043226 (organelle), GO:0005737 (cytoplasm), GO:0043229 (intracellular organelle), GO:0005739 (mitochondrion), GO:0043227 (membrane-bounded organelle), GO:0043231 (intracellular membrane-bounded organelle)