Sirtuin 2

Last updated

SIRT2
Protein SIRT2 PDB 1j8f.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases SIRT2 , SIR2, SIR2L, SIR2L2, sirtuin 2
External IDs OMIM: 604480; MGI: 1927664; HomoloGene: 40823; GeneCards: SIRT2; OMA:SIRT2 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

22933

64383

Ensembl

ENSG00000283100
ENSG00000068903

ENSMUSG00000015149

UniProt

Q8IXJ6

Q8VDQ8

RefSeq (mRNA)

NM_001193286
NM_012237
NM_030593

NM_001122765
NM_001122766
NM_022432

RefSeq (protein)

NP_001180215
NP_036369
NP_085096

NP_001116237
NP_001116238
NP_071877

Location (UCSC) Chr 19: 38.88 – 38.9 Mb Chr 7: 28.47 – 28.49 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

NAD-dependent deacetylase sirtuin 2 is an enzyme that in humans is encoded by the SIRT2 gene. [5] [6] [7] SIRT2 is an NAD+ (nicotinamide adenine dinucleotide)-dependent deacetylase. Studies of this protein have often been divergent, highlighting the dependence of pleiotropic effects of SIRT2 on cellular context. The natural polyphenol resveratrol is known to exert opposite actions on neural cells according to their normal or cancerous status. [8] Similar to other sirtuin family members, SIRT2 displays a ubiquitous distribution. SIRT2 is expressed in a wide range of tissues and organs and has been detected particularly in metabolically relevant tissues, including the brain, muscle, liver, testes, pancreas, kidney, and adipose tissue of mice. Of note, SIRT2 expression is much higher in the brain than all other organs studied, particularly in the cortex, striatum, hippocampus, and spinal cord. [9]

Function

Studies suggest that the human sirtuins may function as intracellular regulatory proteins with mono-ADP-ribosyltransferase activity. [7] Cytosolic functions of SIRT2 include the regulation of microtubule acetylation, control of myelination in the central and peripheral nervous system [ citation needed ] and gluconeogenesis. [10] There is growing evidence for additional functions of SIRT2 in the nucleus. During the G2/M transition, nuclear SIRT2 is responsible for global deacetylation of H4K16, facilitating H4K20 methylation and subsequent chromatin compaction. [11] In response to DNA damage, SIRT2 was also found to deacetylate H3K56 in vivo. [12] Finally, SIRT2 negatively regulates the acetyltransferase activity of the transcriptional co-activator p300 via deacetylation of an automodification loop within its catalytic domain. [13]

Structure

Gene

Human SIRT2 gene has 18 exons resides on chromosome 19 at q13. [7] For SIRT2, four different human splice variants are deposited in the GenBank sequence database. [14]

Protein

SIRT2 gene encodes a member of the sirtuin family of proteins, homologs to the yeast Sir2 protein. Members of the sirtuin family are characterized by a sirtuin core domain and grouped into four classes. The protein encoded by this gene is included in class I of the sirtuin family. Several transcript variants are resulted from alternative splicing of this gene. [7] Only transcript variants 1 and 2 have confirmed protein products of physiological relevance. A leucine-rich nuclear export signal (NES) within the N-terminal region of these two isoforms is identified. [14] Since deletion of the NES led to nucleocytoplasmic distribution, it is suggested to mediate their cytosolic localization. [15]

Selective ligands

Inhibitors

Animal studies

Metabolic actions

SIRT2 suppresses inflammatory responses in mice through p65 deacetylation and inhibition of NF-κB activity. [19] SIRT2 is responsible for the deacetylation and activation of G6PD, stimulating pentose phosphate pathway to supply cytosolic NADPH to counteract oxidative damage and protect mouse erythrocytes. [20]

Neurodegeneration

Several studies in cell and invertebrate models of Parkinson's disease (PD) and Huntington's disease (HD) suggested potential neuroprotective effects of SIRT2 inhibition, in striking contrast with other sirtuin family members. [21] [22] In addition, recent evidence shows that inhibition of SIRT2 protects against MPTP-induced neuronal loss in vivo. [23]

Clinical significance

Metabolic actions

Several SIRT2 deacetylation targets play important roles in metabolic homeostasis. SIRT2 inhibits adipogenesis by deacetylating FOXO1 and thus may protect against insulin resistance. SIRT2 sensitizes cells to the action of insulin by physically interacting with and activating Akt and downstream targets. SIRT2 mediates mitochondrial biogenesis by deacetylating PGC-1α, upregulates antioxidant enzyme expression by deacetylating FOXO3a, and thereby reduces ROS levels. Also, Sirt2 can reactivate the inactive G6PD by removing the acetyaltion at K403 [24] .

Cell cycle regulation

Although preferentially cytosolic, SIRT2 transiently shuttles to the nucleus during the G2/M transition of the cell cycle, where it has a strong preference for histone H4 lysine 16 (H4K16ac), [25] thereby regulating chromosomal condensation during mitosis. [26] During the cell cycle, SIRT2 associates with several mitotic structures including the centrosome, mitotic spindle, and midbody, presumably to ensure normal cell division. [15] Finally, cells with SIRT2 overexpression exhibit marked prolongation of the cell cycle. [27]

Tumorigenesis

Mounting evidence implies a role for SIRT2 in tumorigenesis. SIRT2 may suppress or promote tumor growth in a context-dependent manner. SIRT2 has been proposed to act as a tumor suppressor by preventing chromosomal instability during mitosis. [28] SIRT2-specific inhibitors exhibits broad anticancer activity. [29] [30]

Interactions

SIRT2 has been shown to interact with:

Related Research Articles

<span class="mw-page-title-main">Histone deacetylase</span> Class of enzymes important in regulating DNA transcription

Histone deacetylases (EC 3.5.1.98, HDAC) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on both histone and non-histone proteins. HDACs allow histones to wrap the DNA more tightly. This is important because DNA is wrapped around histones, and DNA expression is regulated by acetylation and de-acetylation. HDAC's action is opposite to that of histone acetyltransferase. HDAC proteins are now also called lysine deacetylases (KDAC), to describe their function rather than their target, which also includes non-histone proteins. In general, they suppress gene expression.

<span class="mw-page-title-main">Sirtuin</span> Enzyme

Sirtuins are a family of signaling proteins involved in metabolic regulation. They are ancient in animal evolution and appear to possess a highly conserved structure throughout all kingdoms of life. Chemically, sirtuins are a class of proteins that possess either mono-ADP-ribosyltransferase or deacylase activity, including deacetylase, desuccinylase, demalonylase, demyristoylase and depalmitoylase activity. The name Sir2 comes from the yeast gene 'silent mating-type information regulation 2', the gene responsible for cellular regulation in yeast.

<span class="mw-page-title-main">Histone acetylation and deacetylation</span> Biological processes used in gene regulation

Histone acetylation and deacetylation are the processes by which the lysine residues within the N-terminal tail protruding from the histone core of the nucleosome are acetylated and deacetylated as part of gene regulation.

<span class="mw-page-title-main">HDAC1</span> Protein-coding gene in the species Homo sapiens

Histone deacetylase 1 (HDAC1) is an enzyme that in humans is encoded by the HDAC1 gene.

Histone deacetylase inhibitors are chemical compounds that inhibit histone deacetylases. Since deacetylation of histones produces transcriptionally silenced heterochromatin, HDIs can render chromatin more transcriptionally active and induce epigenomic changes.

Chromatin remodeling is the dynamic modification of chromatin architecture to allow access of condensed genomic DNA to the regulatory transcription machinery proteins, and thereby control gene expression. Such remodeling is principally carried out by 1) covalent histone modifications by specific enzymes, e.g., histone acetyltransferases (HATs), deacetylases, methyltransferases, and kinases, and 2) ATP-dependent chromatin remodeling complexes which either move, eject or restructure nucleosomes. Besides actively regulating gene expression, dynamic remodeling of chromatin imparts an epigenetic regulatory role in several key biological processes, egg cells DNA replication and repair; apoptosis; chromosome segregation as well as development and pluripotency. Aberrations in chromatin remodeling proteins are found to be associated with human diseases, including cancer. Targeting chromatin remodeling pathways is currently evolving as a major therapeutic strategy in the treatment of several cancers.

<span class="mw-page-title-main">Histone deacetylase 2</span> Protein-coding gene in the species Homo sapiens

Histone deacetylase 2 (HDAC2) is an enzyme that in humans is encoded by the HDAC2 gene. It belongs to the histone deacetylase class of enzymes responsible for the removal of acetyl groups from lysine residues at the N-terminal region of the core histones. As such, it plays an important role in gene expression by facilitating the formation of transcription repressor complexes and for this reason is often considered an important target for cancer therapy.

<span class="mw-page-title-main">HDAC6</span> Protein-coding gene in the species Homo sapiens

Histone deacetylase 6 is an enzyme that in humans is encoded by the HDAC6 gene. HDAC6 has emerged as a highly promising candidate to selectively inhibit as a therapeutic strategy to combat several types of cancer and neurodegenerative disorders.

<span class="mw-page-title-main">Sirtuin 1</span> Protein

Sirtuin 1, also known as NAD-dependent deacetylase sirtuin-1, is a protein that in humans is encoded by the SIRT1 gene.

<span class="mw-page-title-main">SAP30</span> Protein-coding gene in the species Homo sapiens

Sin3A-associated protein, 30kDa, also known as SAP30, is a protein which in humans is encoded by the SAP30 gene.

<span class="mw-page-title-main">CHD4</span> Protein-coding gene in the species Homo sapiens

Chromodomain-helicase-DNA-binding protein 4 is an enzyme that in humans is encoded by the CHD4 gene. CHD4 is the core nucleosome-remodelling component of the Nucleosome Remodelling and Deacetylase (NuRD) complex.

<span class="mw-page-title-main">Sirtuin 3</span> Protein-coding gene in the species Homo sapiens

NAD-dependent deacetylase sirtuin-3, mitochondrial also known as SIRT3 is a protein that in humans is encoded by the SIRT3 gene [sirtuin 3 ]. SIRT3 is member of the mammalian sirtuin family of proteins, which are homologs to the yeast Sir2 protein. SIRT3 exhibits NAD+-dependent deacetylase activity.

<span class="mw-page-title-main">Sirtuin 5</span> Protein-coding gene in the species Homo sapiens

Sirtuin 5 , also known as SIRT5 is a protein which in humans in encoded by the SIRT5 gene and in other species by the orthologous Sirt5 gene.

<span class="mw-page-title-main">Sirtuin 6</span> Protein-coding gene in the species Homo sapiens

Sirtuin 6 is a stress responsive protein deacetylase and mono-ADP ribosyltransferase enzyme encoded by the SIRT6 gene. In laboratory research, SIRT6 appears to function in multiple molecular pathways related to aging, including DNA repair, telomere maintenance, glycolysis and inflammation. SIRT6 is member of the mammalian sirtuin family of proteins, which are homologs to the yeast Sir2 protein.

<span class="mw-page-title-main">Sirtuin 4</span> Protein-coding gene in the species Homo sapiens

Sirtuin 4, also known as SIRT4, is a mitochondrial protein which in humans is encoded by the SIRT4 gene. SIRT4 is member of the mammalian sirtuin family of proteins, which are homologs to the yeast Sir2 protein. SIRT4 exhibits NAD+-dependent deacetylase activity.

<span class="mw-page-title-main">CobB</span> Bacterial protein

CobB is a bacterial protein that belongs to the sirtuin family, a broadly conserved family of NAD+-dependent protein deacetylases.

Cocaine addiction is the compulsive use of cocaine despite adverse consequences. It arises through epigenetic modification and transcriptional regulation of genes in the nucleus accumbens.

SilentInformationRegulator (SIR) proteins are involved in regulating gene expression. SIR proteins organize heterochromatin near telomeres, ribosomal DNA (rDNA), and at silent loci including hidden mating type loci in yeast. The SIR family of genes encodes catalytic and non-catalytic proteins that are involved in de-acetylation of histone tails and the subsequent condensation of chromatin around a SIR protein scaffold. Some SIR family members are conserved from yeast to humans.

H4K16ac is an epigenetic modification to the DNA packaging protein Histone H4. It is a mark that indicates the acetylation at the 16th lysine residue of the histone H4 protein.

H3K56ac is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the acetylation at the 56th lysine residue of the histone H3 protein.

References

  1. 1 2 3 ENSG00000068903 GRCh38: Ensembl release 89: ENSG00000283100, ENSG00000068903 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000015149 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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  6. ↑ Frye RA (June 1999). "Characterization of five human cDNAs with homology to the yeast SIR2 gene: Sir2-like proteins (sirtuins) metabolize NAD and may have protein ADP-ribosyltransferase activity". Biochemical and Biophysical Research Communications. 260 (1): 273–279. doi:10.1006/bbrc.1999.0897. PMID   10381378.
  7. 1 2 3 4 "Entrez Gene: SIRT2 sirtuin (silent mating type information regulation 2 homolog) 2 (S. cerevisiae)".
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  30. 1 2 Xu SN, Wang TS, Li X, Wang YP (September 2016). "SIRT2 activates G6PD to enhance NADPH production and promote leukaemia cell proliferation". Scientific Reports. 6: 32734. Bibcode:2016NatSR...632734X. doi:10.1038/srep32734. PMC   5009355 . PMID   27586085.
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  38. ↑ Jiang W, Wang S, Xiao M, Lin Y, Zhou L, Lei Q, et al. (July 2011). "Acetylation regulates gluconeogenesis by promoting PEPCK1 degradation via recruiting the UBR5 ubiquitin ligase". Molecular Cell. 43 (1): 33–44. doi:10.1016/j.molcel.2011.04.028. PMC   3962309 . PMID   21726808.
  39. ↑ Wang F, Tong Q (February 2009). "SIRT2 suppresses adipocyte differentiation by deacetylating FOXO1 and enhancing FOXO1's repressive interaction with PPARgamma". Molecular Biology of the Cell. 20 (3): 801–808. doi:10.1091/mbc.E08-06-0647. PMC   2633403 . PMID   19037106.
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  41. ↑ Jin YH, Kim YJ, Kim DW, Baek KH, Kang BY, Yeo CY, et al. (April 2008). "Sirt2 interacts with 14-3-3 beta/gamma and down-regulates the activity of p53". Biochemical and Biophysical Research Communications. 368 (3): 690–695. doi:10.1016/j.bbrc.2008.01.114. PMID   18249187.
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