Sirtuin 2 Explained

NAD-dependent deacetylase sirtuin 2 is an enzyme that in humans is encoded by the SIRT2 gene.^{[1] [2] [3]} 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.^[4] 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.^[5]

Function

Studies suggest that the human sirtuins may function as intracellular regulatory proteins with mono-ADP-ribosyltransferase activity. Cytosolic functions of SIRT2 include the regulation of microtubule acetylation, control of myelination in the central and peripheral nervous system and gluconeogenesis.^[6] 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.^[7] In response to DNA damage, SIRT2 was also found to deacetylate H3K56 in vivo.^[8] Finally, SIRT2 negatively regulates the acetyltransferase activity of the transcriptional co-activator p300 via deacetylation of an automodification loop within its catalytic domain.^[9]

Structure

Gene

Human SIRT2 gene has 18 exons resides on chromosome 19 at q13.^[3] For SIRT2, four different human splice variants are deposited in the GenBank sequence database.^[10]

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.^[3] 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.^[10] Since deletion of the NES led to nucleocytoplasmic distribution, it is suggested to mediate their cytosolic localization.^[11]

Selective ligands

Inhibitors

• Benzamide compound # 64^[12]
• (S)-2-Pentyl-6-chloro,8-bromo-chroman-4-one: IC₅₀ of 1.5 μM, highly selective over SIRT2 and SIRT3^[13]
• 3′-Phenethyloxy-2-anilinobenzamide (33i): IC₅₀ of 0.57 μM^[14]
• AGK2 (C₂₃H₁₃C_l2N₃O₂; 2-cyano-3-[5-(2,5-dichlorophenyl)-2-furanyl]-N-5-quinolinyl-2-propenamide) is a potent, cell-permeable, selective SIRT2 inhibitor that minimally affects both SIRT1 and SIRT3^[15]

Animal studies

Metabolic actions

SIRT2 suppresses inflammatory responses in mice through p65 deacetylation and inhibition of NF-κB activity.^[16] 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.^[17]

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.^{[18] [19]} In addition, recent evidence shows that inhibition of SIRT2 protects against MPTP-induced neuronal loss in vivo.^[20]

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.

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),^[21] thereby regulating chromosomal condensation during mitosis.^[22] During the cell cycle, SIRT2 associates with several mitotic structures including the centrosome, mitotic spindle, and midbody, presumably to ensure normal cell division.^[11] Finally, cells with SIRT2 overexpression exhibit marked prolongation of the cell cycle.^[23]

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.^[24] SIRT2-specific inhibitors exhibits broad anticancer activity.^{[25] [26]}

Interactions

SIRT2 has been shown to interact with:

• α-tubulin,^[27]
• TUG,^[28]
• β-catenin,^[29]
• PGAM2,^[30]
• TIAM1,^[31]
• ApoE4,^[32]
• p53,^[33]
• PEPCK,^[34]
• FOXO1,^[35]
• p300,^[36]
• 14-3-3 protein,^[37]
• G6PD,^{[17] [26]} and
• CBP.^[38]

Further reading

• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–74 . Jan 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Andersson B, Wentland MA, Ricafrente JY, Liu W, Gibbs RA . A "double adaptor" method for improved shotgun library construction . Analytical Biochemistry . 236 . 1 . 107–13 . Apr 1996 . 8619474 . 10.1006/abio.1996.0138 .
• Yu W, Andersson B, Worley KC, Muzny DM, Ding Y, Liu W, Ricafrente JY, Wentland MA, Lennon G, Gibbs RA . Large-scale concatenation cDNA sequencing . Genome Research . 7 . 4 . 353–58 . Apr 1997 . 9110174 . 139146 . 10.1101/gr.7.4.353 .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–56 . Oct 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• Frye RA . Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins . Biochemical and Biophysical Research Communications . 273 . 2 . 793–98 . Jul 2000 . 10873683 . 10.1006/bbrc.2000.3000 .
• Hu RM, Han ZG, Song HD, Peng YD, Huang QH, Ren SX, Gu YJ, Huang CH, Li YB, Jiang CL, Fu G, Zhang QH, Gu BW, Dai M, Mao YF, Gao GF, Rong R, Ye M, Zhou J, Xu SH, Gu J, Shi JX, Jin WR, Zhang CK, Wu TM, Huang GY, Chen Z, Chen MD, Chen JL . Gene expression profiling in the human hypothalamus-pituitary-adrenal axis and full-length cDNA cloning . Proceedings of the National Academy of Sciences of the United States of America . 97 . 17 . 9543–48 . Aug 2000 . 10931946 . 16901 . 10.1073/pnas.160270997 . 2000PNAS...97.9543H . free .
• Finnin MS, Donigian JR, Pavletich NP . Structure of the histone deacetylase SIRT2 . Nature Structural Biology . 8 . 7 . 621–25 . Jul 2001 . 11427894 . 10.1038/89668 . 27800665 .
• Grozinger CM, Chao ED, Blackwell HE, Moazed D, Schreiber SL . Identification of a class of small molecule inhibitors of the sirtuin family of NAD-dependent deacetylases by phenotypic screening . The Journal of Biological Chemistry . 276 . 42 . 38837–43 . Oct 2001 . 11483616 . 10.1074/jbc.M106779200 . free .
• Borra MT, O'Neill FJ, Jackson MD, Marshall B, Verdin E, Foltz KR, Denu JM . Conserved enzymatic production and biological effect of O-acetyl-ADP-ribose by silent information regulator 2-like NAD+-dependent deacetylases . The Journal of Biological Chemistry . 277 . 15 . 12632–41 . Apr 2002 . 11812793 . 10.1074/jbc.M111830200 . free .
• De Smet C, Nishimori H, Furnari FB, Bögler O, Huang HJ, Cavenee WK . A novel seven transmembrane receptor induced during the early steps of astrocyte differentiation identified by differential expression . Journal of Neurochemistry . 81 . 3 . 575–88 . May 2002 . 12065666 . 10.1046/j.1471-4159.2002.00847.x . 23925334 .
• North BJ, Marshall BL, Borra MT, Denu JM, Verdin E . The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase . Molecular Cell . 11 . 2 . 437–44 . Feb 2003 . 12620231 . 10.1016/S1097-2765(03)00038-8 . free .
• Dryden SC, Nahhas FA, Nowak JE, Goustin AS, Tainsky MA . Role for human SIRT2 NAD-dependent deacetylase activity in control of mitotic exit in the cell cycle . Molecular and Cellular Biology . 23 . 9 . 3173–85 . May 2003 . 12697818 . 153197 . 10.1128/MCB.23.9.3173-3185.2003 .
• Fulco M, Schiltz RL, Iezzi S, King MT, Zhao P, Kashiwaya Y, Hoffman E, Veech RL, Sartorelli V . Sir2 regulates skeletal muscle differentiation as a potential sensor of the redox state . Molecular Cell . 12 . 1 . 51–62 . Jul 2003 . 12887892 . 10.1016/S1097-2765(03)00226-0 . free .
• Hiratsuka M, Inoue T, Toda T, Kimura N, Shirayoshi Y, Kamitani H, Watanabe T, Ohama E, Tahimic CG, Kurimasa A, Oshimura M . Proteomics-based identification of differentially expressed genes in human gliomas: down-regulation of SIRT2 gene . Biochemical and Biophysical Research Communications . 309 . 3 . 558–66 . Sep 2003 . 12963026 . 10.1016/j.bbrc.2003.08.029 .
• van der Horst A, Tertoolen LG, de Vries-Smits LM, Frye RA, Medema RH, Burgering BM . FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2(SIRT1) . The Journal of Biological Chemistry . 279 . 28 . 28873–79 . Jul 2004 . 15126506 . 10.1074/jbc.M401138200 . free .
• Bae NS, Swanson MJ, Vassilev A, Howard BH . Human histone deacetylase SIRT2 interacts with the homeobox transcription factor HOXA10 . Journal of Biochemistry . 135 . 6 . 695–700 . Jun 2004 . 15213244 . 10.1093/jb/mvh084 .
• de Oliveira RM, Sarkander J, Kazantsev AG, Outeiro TF . SIRT2 as a Therapeutic Target for Age-Related Disorders . Frontiers in Pharmacology . 3 . 82 . 2012 . 22563317 . 3342661 . 10.3389/fphar.2012.00082 . free .

Notes and References

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3. Web site: Entrez Gene: SIRT2 sirtuin (silent mating type information regulation 2 homolog) 2 (S. cerevisiae).
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6. North BJ, Marshall BL, Borra MT, Denu JM, Verdin E . The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase . Molecular Cell . 11 . 2 . 437–44 . Feb 2003 . 12620231 . 10.1016/s1097-2765(03)00038-8. free .
7. Serrano L, Martínez-Redondo P, Marazuela-Duque A, Vazquez BN, Dooley SJ, Voigt P, Beck DB, Kane-Goldsmith N, Tong Q, Rabanal RM, Fondevila D, Muñoz P, Krüger M, Tischfield JA, Vaquero A . The tumor suppressor SirT2 regulates cell cycle progression and genome stability by modulating the mitotic deposition of H4K20 methylation . Genes & Development . 27 . 6 . 639–53 . Mar 2013 . 23468428 . 10.1101/gad.211342.112 . 3613611.
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