InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: SIRT2

Summary

InnateDB Protein

IDBP-49712.7

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

SIRT2

Protein Name

sirtuin 2

Synonyms

SIR2; SIR2L; SIR2L2;

Species

Homo sapiens

Ensembl Protein

ENSP00000351809

InnateDB Gene

IDBG-49708 (SIRT2)

Protein Structure

UniProt Annotation

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 SETD8 leading to ulterior levels of H4K20me2 and H4K20me3 deposition throughout cell cycle, and mitotic S-phase progression. Deacetylates SETD8 modulating SETD8 chromatin localization during the mitotic stress response. Deacetylates also histone H3 at 'Lys- 57' (H3K56ac) during the mitotic G2/M transition. 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. 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 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. 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. 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.Isoform 1: Deacetylates EP300, alpha-tubulin and histone H3 and H4.Isoform 2: Deacetylates EP300, alpha-tubulin and histone H3 and H4.Isoform 5: Lacks deacetylation activity.

Subcellular Localization

Nucleus. Cytoplasm, perinuclear region. Cytoplasm. Cytoplasm, cytoskeleton. Cytoplasm, cytoskeleton, microtubule organizing center, centrosome. Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriole. Cytoplasm, cytoskeleton, spindle. Midbody. Chromosome. Perikaryon {ECO:0000250}. Cell projection {ECO:0000250}. Cell projection, growth cone {ECO:0000250}. Myelin membrane {ECO:0000250}. Note=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. Colocalizes with acetylated alpha-tubulin in cell projection processes during primary oligodendrocyte precursor (OLP) differentiation (By similarity). 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 SETD8 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. Detected in perinuclear foci that may be aggresomes containing misfolded, ubiquitinated proteins. 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. {ECO:0000250}.Isoform 1: Cytoplasm {ECO:0000269PubMed:24177535}. Nucleus {ECO:0000269PubMed:24177535}. Note=Predominantly localized in the cytoplasmic.Isoform 2: Cytoplasm {ECO:0000269PubMed:24177535}. Nucleus {ECO:0000269PubMed:24177535}. Note=Predominantly localized in the cytoplasmic.Isoform 5: Cytoplasm {ECO:0000269PubMed:24177535}. Nucleus {ECO:0000269PubMed:24177535}. Note=Predominantly localized in the nucleus.

Disease Associations

Tissue Specificity

Isoform 1 is expressed in heart, liver and skeletal muscle, weakly expressed in the cortex. Isoform 2 is strongly expressed in the cortex, weakly expressed in heart and liver. Weakly expressed in several malignancies including breast, liver, brain, kidney and prostate cancers compared to normal tissues. Weakly expressed in glioma cell lines compared to normal brain tissues (at protein level). Widely expressed. Highly expressed in heart, brain and skeletal muscle, while it is weakly expressed in placenta and lung. Down-regulated in many gliomas suggesting that it may act as a tumor suppressor gene in human gliomas possibly through the regulation of microtubule network. {ECO:0000269PubMed:10381378, ECO:0000269PubMed:10393250, ECO:0000269PubMed:12963026, ECO:0000269PubMed:16909107, ECO:0000269PubMed:21791548, ECO:0000269PubMed:22014574}.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 105 experimentally validated interaction(s) in this database.
They are also associated with 10 interaction(s) predicted by orthology.

Experimentally validated
Total	105 [view]
Protein-Protein	34 [view]
Protein-DNA	1 [view]
Protein-RNA	0
DNA-DNA	70 [view]
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	10 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0003682	chromatin binding
GO:0004407	histone deacetylase activity
GO:0005515	protein binding
GO:0008134	transcription factor binding
GO:0008270	zinc ion binding
GO:0017136	NAD-dependent histone deacetylase activity
GO:0033558	protein deacetylase activity
GO:0034979	NAD-dependent protein deacetylase activity
GO:0035035	histone acetyltransferase binding
GO:0042826	histone deacetylase binding
GO:0042903	tubulin deacetylase activity
GO:0043130	ubiquitin binding
GO:0046970	NAD-dependent histone deacetylase activity (H4-K16 specific)
GO:0070403	NAD+ binding

Biological Process

GO:0000122	negative regulation of transcription from RNA polymerase II promoter
GO:0000183	chromatin silencing at rDNA
GO:0006342	chromatin silencing
GO:0006348	chromatin silencing at telomere
GO:0006351	transcription, DNA-templated
GO:0006471	protein ADP-ribosylation
GO:0006476	protein deacetylation
GO:0006914	autophagy
GO:0007067	mitotic nuclear division
GO:0007096	regulation of exit from mitosis
GO:0007126	meiotic nuclear division
GO:0008219	cell death
GO:0008285	negative regulation of cell proliferation
GO:0010507	negative regulation of autophagy
GO:0010801	negative regulation of peptidyl-threonine phosphorylation
GO:0014065	phosphatidylinositol 3-kinase signaling
GO:0016458	gene silencing
GO:0016575	histone deacetylation
GO:0021762	substantia nigra development
GO:0022011	myelination in peripheral nervous system
GO:0031641	regulation of myelination
GO:0032436	positive regulation of proteasomal ubiquitin-dependent protein catabolic process
GO:0034599	cellular response to oxidative stress
GO:0034983	peptidyl-lysine deacetylation
GO:0035729	cellular response to hepatocyte growth factor stimulus
GO:0042177	negative regulation of protein catabolic process
GO:0042325	regulation of phosphorylation
GO:0043161	proteasome-mediated ubiquitin-dependent protein catabolic process
GO:0043388	positive regulation of DNA binding
GO:0043491	protein kinase B signaling
GO:0044242	cellular lipid catabolic process
GO:0045087	innate immune response
GO:0045599	negative regulation of fat cell differentiation
GO:0045836	positive regulation of meiosis
GO:0045843	negative regulation of striated muscle tissue development
GO:0045892	negative regulation of transcription, DNA-templated
GO:0045944	positive regulation of transcription from RNA polymerase II promoter
GO:0048012	hepatocyte growth factor receptor signaling pathway
GO:0051726	regulation of cell cycle
GO:0051775	response to redox state
GO:0051781	positive regulation of cell division
GO:0051987	positive regulation of attachment of spindle microtubules to kinetochore
GO:0061428	negative regulation of transcription from RNA polymerase II promoter in response to hypoxia
GO:0061433	cellular response to caloric restriction
GO:0070446	negative regulation of oligodendrocyte progenitor proliferation
GO:0070932	histone H3 deacetylation
GO:0070933	histone H4 deacetylation
GO:0071219	cellular response to molecule of bacterial origin
GO:0071456	cellular response to hypoxia
GO:0071872	cellular response to epinephrine stimulus
GO:0090042	tubulin deacetylation
GO:1900119	positive regulation of execution phase of apoptosis
GO:1900195	positive regulation of oocyte maturation
GO:1900425	negative regulation of defense response to bacterium
GO:2000378	negative regulation of reactive oxygen species metabolic process
GO:2000777	positive regulation of proteasomal ubiquitin-dependent protein catabolic process involved in cellular response to hypoxia

Cellular Component

GO:0005634	nucleus
GO:0005677	chromatin silencing complex
GO:0005694	chromosome
GO:0005720	nuclear heterochromatin
GO:0005737	cytoplasm
GO:0005813	centrosome
GO:0005814	centriole
GO:0005819	spindle
GO:0005829	cytosol
GO:0005874	microtubule
GO:0005886	plasma membrane
GO:0030426	growth cone
GO:0030496	midbody
GO:0033010	paranodal junction
GO:0033270	paranode region of axon
GO:0043204	perikaryon
GO:0043209	myelin sheath
GO:0043219	lateral loop
GO:0043220	Schmidt-Lanterman incisure
GO:0044224	juxtaparanode region of axon
GO:0048471	perinuclear region of cytoplasm
GO:0072686	mitotic spindle
GO:0072687	meiotic spindle
GO:0097386	glial cell projection