Sirtuin 2

{{Short description|Protein-coding gene in the species Homo sapiens}}

NAD-dependent deacetylase sirtuin 2 is an enzyme that in humans is encoded by the SIRT2 gene.{{cite journal | vauthors = Afshar G, Murnane JP | title = Characterization of a human gene with sequence homology to Saccharomyces cerevisiae SIR2 | journal = Gene | volume = 234 | issue = 1 | pages = 161–168 | date = June 1999 | pmid = 10393250 | doi = 10.1016/S0378-1119(99)00162-6 }}{{cite journal | vauthors = Frye RA | title = 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 | journal = Biochemical and Biophysical Research Communications | volume = 260 | issue = 1 | pages = 273–279 | date = June 1999 | pmid = 10381378 | doi = 10.1006/bbrc.1999.0897 }}{{cite web | title = Entrez Gene: SIRT2 sirtuin (silent mating type information regulation 2 homolog) 2 (S. cerevisiae)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=22933}} 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.{{cite journal | vauthors = Sayd S, Junier MP, Chneiweiss H | title = [SIRT2, a multi-talented deacetylase] | journal = Médecine/Sciences | volume = 30 | issue = 5 | pages = 532–536 | date = May 2014 | pmid = 24939540 | doi = 10.1051/medsci/20143005016 | doi-access = free }} 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.{{cite journal | vauthors = Maxwell MM, Tomkinson EM, Nobles J, Wizeman JW, Amore AM, Quinti L, Chopra V, Hersch SM, Kazantsev AG | title = The Sirtuin 2 microtubule deacetylase is an abundant neuronal protein that accumulates in the aging CNS | journal = Human Molecular Genetics | volume = 20 | issue = 20 | pages = 3986–3996 | date = October 2011 | pmid = 21791548 | pmc = 3203628 | doi = 10.1093/hmg/ddr326 }}

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{{Citation needed|reason= The citation at the end of this sentence does not address myelination in the central or peripheral nervous system.|date=June 2017}} and gluconeogenesis.{{cite journal | vauthors = North BJ, Marshall BL, Borra MT, Denu JM, Verdin E | title = The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase | journal = Molecular Cell | volume = 11 | issue = 2 | pages = 437–444 | date = February 2003 | pmid = 12620231 | doi = 10.1016/s1097-2765(03)00038-8 | doi-access = free }} 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.{{cite journal | vauthors = 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 | title = The tumor suppressor SirT2 regulates cell cycle progression and genome stability by modulating the mitotic deposition of H4K20 methylation | journal = Genes & Development | volume = 27 | issue = 6 | pages = 639–653 | date = March 2013 | pmid = 23468428 | pmc = 3613611 | doi = 10.1101/gad.211342.112 }} In response to DNA damage, SIRT2 was also found to deacetylate H3K56 in vivo.{{cite journal | vauthors = Vempati RK, Jayani RS, Notani D, Sengupta A, Galande S, Haldar D | title = p300-mediated acetylation of histone H3 lysine 56 functions in DNA damage response in mammals | journal = The Journal of Biological Chemistry | volume = 285 | issue = 37 | pages = 28553–28564 | date = September 2010 | pmid = 20587414 | pmc = 2937881 | doi = 10.1074/jbc.M110.149393 | doi-access = free }} Finally, SIRT2 negatively regulates the acetyltransferase activity of the transcriptional co-activator p300 via deacetylation of an automodification loop within its catalytic domain.{{cite journal | vauthors = Black JC, Mosley A, Kitada T, Washburn M, Carey M | title = The SIRT2 deacetylase regulates autoacetylation of p300 | journal = Molecular Cell | volume = 32 | issue = 3 | pages = 449–455 | date = November 2008 | pmid = 18995842 | pmc = 2645867 | doi = 10.1016/j.molcel.2008.09.018 }}

Structure

= Gene =

Human SIRT2 gene has 18 exons resides on chromosome 19 at q13. For SIRT2, four different human splice variants are deposited in the GenBank sequence database.{{cite journal | vauthors = Rack JG, VanLinden MR, Lutter T, Aasland R, Ziegler M | title = Constitutive nuclear localization of an alternatively spliced sirtuin-2 isoform | journal = Journal of Molecular Biology | volume = 426 | issue = 8 | pages = 1677–1691 | date = April 2014 | pmid = 24177535 | doi = 10.1016/j.jmb.2013.10.027 | hdl-access = free | hdl = 1956/10670 }}

= 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. 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. Since deletion of the NES led to nucleocytoplasmic distribution, it is suggested to mediate their cytosolic localization.{{cite journal | vauthors = North BJ, Verdin E | title = Interphase nucleo-cytoplasmic shuttling and localization of SIRT2 during mitosis | journal = PLOS ONE | volume = 2 | issue = 8 | pages = e784 | date = August 2007 | pmid = 17726514 | pmc = 1949146 | doi = 10.1371/journal.pone.0000784 | bibcode = 2007PLoSO...2..784N | doi-access = free }}

Selective ligands

= Inhibitors =

(S)-2-Pentyl-6-chloro,8-bromo-chroman-4-one: IC₅₀ of 1.5 μM, highly selective over SIRT2 and SIRT3{{cite journal | vauthors = Fridén-Saxin M, Seifert T, Landergren MR, Suuronen T, Lahtela-Kakkonen M, Jarho EM, Luthman K | title = Synthesis and evaluation of substituted chroman-4-one and chromone derivatives as sirtuin 2-selective inhibitors | journal = Journal of Medicinal Chemistry | volume = 55 | issue = 16 | pages = 7104–7113 | date = August 2012 | pmid = 22746324 | pmc = 3426190 | doi = 10.1021/jm3005288 }}
3′-Phenethyloxy-2-anilinobenzamide (33i): IC₅₀ of 0.57 μM{{cite journal | vauthors = Suzuki T, Khan MN, Sawada H, Imai E, Itoh Y, Yamatsuta K, Tokuda N, Takeuchi J, Seko T, Nakagawa H, Miyata N | title = Design, synthesis, and biological activity of a novel series of human sirtuin-2-selective inhibitors | journal = Journal of Medicinal Chemistry | volume = 55 | issue = 12 | pages = 5760–5773 | date = June 2012 | pmid = 22642300 | doi = 10.1021/jm3002108 }}
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{{cite journal | vauthors = Wawruszak A, Luszczki J, Czerwonka A, Okon E, Stepulak A | title = Assessment of Pharmacological Interactions between SIRT2 Inhibitor AGK2 and Paclitaxel in Different Molecular Subtypes of Breast Cancer Cells | journal = Cells | volume = 11 | issue = 7 | pages = 1211 | date = April 2022 | pmid = 35406775 | pmc = 8998062 | doi = 10.3390/cells11071211 | doi-access = free }}{{Creative Commons text attribution notice|cc=by4|from this source=yes}}

Animal studies

= Metabolic actions =

SIRT2 suppresses inflammatory responses in mice through p65 deacetylation and inhibition of NF-κB activity.{{cite journal | vauthors = Gomes P, Fleming Outeiro T, Cavadas C | title = Emerging Role of Sirtuin 2 in the Regulation of Mammalian Metabolism | journal = Trends in Pharmacological Sciences | volume = 36 | issue = 11 | pages = 756–768 | date = November 2015 | pmid = 26538315 | doi = 10.1016/j.tips.2015.08.001 }} 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.{{cite journal | vauthors = Wang YP, Zhou LS, Zhao YZ, Wang SW, Chen LL, Liu LX, Ling ZQ, Hu FJ, Sun YP, Zhang JY, Yang C, Yang Y, Xiong Y, Guan KL, Ye D | title = Regulation of G6PD acetylation by SIRT2 and KAT9 modulates NADPH homeostasis and cell survival during oxidative stress | journal = The EMBO Journal | volume = 33 | issue = 12 | pages = 1304–1320 | date = June 2014 | pmid = 24769394 | pmc = 4194121 | doi = 10.1002/embj.201387224 }}

= 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.{{cite journal | vauthors = Outeiro TF, Kontopoulos E, Altmann SM, Kufareva I, Strathearn KE, Amore AM, Volk CB, Maxwell MM, Rochet JC, McLean PJ, Young AB, Abagyan R, Feany MB, Hyman BT, Kazantsev AG | title = Sirtuin 2 inhibitors rescue alpha-synuclein-mediated toxicity in models of Parkinson's disease | journal = Science | volume = 317 | issue = 5837 | pages = 516–519 | date = July 2007 | pmid = 17588900 | doi = 10.1126/science.1143780 | s2cid = 84493360 | bibcode = 2007Sci...317..516O }}{{cite journal | vauthors = Luthi-Carter R, Taylor DM, Pallos J, Lambert E, Amore A, Parker A, Moffitt H, Smith DL, Runne H, Gokce O, Kuhn A, Xiang Z, Maxwell MM, Reeves SA, Bates GP, Neri C, Thompson LM, Marsh JL, Kazantsev AG | title = SIRT2 inhibition achieves neuroprotection by decreasing sterol biosynthesis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 17 | pages = 7927–7932 | date = April 2010 | pmid = 20378838 | pmc = 2867924 | doi = 10.1073/pnas.1002924107 | doi-access = free | bibcode = 2010PNAS..107.7927L }} In addition, recent evidence shows that inhibition of SIRT2 protects against MPTP-induced neuronal loss in vivo.{{cite journal | vauthors = Chen X, Wales P, Quinti L, Zuo F, Moniot S, Herisson F, Rauf NA, Wang H, Silverman RB, Ayata C, Maxwell MM, Steegborn C, Schwarzschild MA, Outeiro TF, Kazantsev AG | title = The sirtuin-2 inhibitor AK7 is neuroprotective in models of Parkinson's disease but not amyotrophic lateral sclerosis and cerebral ischemia | journal = PLOS ONE | volume = 10 | issue = 1 | pages = e0116919 | date = 2015 | pmid = 25608039 | pmc = 4301865 | doi = 10.1371/journal.pone.0116919 | bibcode = 2015PLoSO..1016919C | doi-access = free }}

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 {{cite journal | vauthors = Wu F, Muskat NH, Dvilansky I, Koren O, Shahar A, Gazit R, Elia N, Arbely E | title = Acetylation-dependent coupling between G6PD activity and apoptotic signaling | journal = Nature Communications | volume = 14 | issue = 1 | pages = 6208 | date = October 2023 | pmid = 37798264 | pmc = 10556143 | doi = 10.1038/s41467-023-41895-2 | bibcode = 2023NatCo..14.6208W }}

=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),{{cite journal | vauthors = Vaquero A, Scher MB, Lee DH, Sutton A, Cheng HL, Alt FW, Serrano L, Sternglanz R, Reinberg D | title = SirT2 is a histone deacetylase with preference for histone H4 Lys 16 during mitosis | journal = Genes & Development | volume = 20 | issue = 10 | pages = 1256–1261 | date = May 2006 | pmid = 16648462 | pmc = 1472900 | doi = 10.1101/gad.1412706 }} thereby regulating chromosomal condensation during mitosis.{{cite journal | vauthors = Inoue T, Hiratsuka M, Osaki M, Yamada H, Kishimoto I, Yamaguchi S, Nakano S, Katoh M, Ito H, Oshimura M | title = SIRT2, a tubulin deacetylase, acts to block the entry to chromosome condensation in response to mitotic stress | journal = Oncogene | volume = 26 | issue = 7 | pages = 945–957 | date = February 2007 | pmid = 16909107 | doi = 10.1038/sj.onc.1209857 | s2cid = 21357335 | doi-access = }} During the cell cycle, SIRT2 associates with several mitotic structures including the centrosome, mitotic spindle, and midbody, presumably to ensure normal cell division. Finally, cells with SIRT2 overexpression exhibit marked prolongation of the cell cycle.{{cite journal | vauthors = Dryden SC, Nahhas FA, Nowak JE, Goustin AS, Tainsky MA | title = Role for human SIRT2 NAD-dependent deacetylase activity in control of mitotic exit in the cell cycle | journal = Molecular and Cellular Biology | volume = 23 | issue = 9 | pages = 3173–3185 | date = May 2003 | pmid = 12697818 | pmc = 153197 | doi = 10.1128/mcb.23.9.3173-3185.2003 }}

= 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.{{cite journal | vauthors = Kim HS, Vassilopoulos A, Wang RH, Lahusen T, Xiao Z, Xu X, Li C, Veenstra TD, Li B, Yu H, Ji J, Wang XW, Park SH, Cha YI, Gius D, Deng CX | title = SIRT2 maintains genome integrity and suppresses tumorigenesis through regulating APC/C activity | journal = Cancer Cell | volume = 20 | issue = 4 | pages = 487–499 | date = October 2011 | pmid = 22014574 | pmc = 3199577 | doi = 10.1016/j.ccr.2011.09.004 }} SIRT2-specific inhibitors exhibits broad anticancer activity.{{cite journal | vauthors = Jing H, Hu J, He B, Negrón Abril YL, Stupinski J, Weiser K, Carbonaro M, Chiang YL, Southard T, Giannakakou P, Weiss RS, Lin H | title = A SIRT2-Selective Inhibitor Promotes c-Myc Oncoprotein Degradation and Exhibits Broad Anticancer Activity | journal = Cancer Cell | volume = 29 | issue = 3 | pages = 297–310 | date = March 2016 | pmid = 26977881 | pmc = 4811675 | doi = 10.1016/j.ccell.2016.02.007 }}{{cite journal | vauthors = Xu SN, Wang TS, Li X, Wang YP | title = SIRT2 activates G6PD to enhance NADPH production and promote leukaemia cell proliferation | journal = Scientific Reports | volume = 6 | pages = 32734 | date = September 2016 | pmid = 27586085 | pmc = 5009355 | doi = 10.1038/srep32734 | bibcode = 2016NatSR...632734X }}

Interactions

SIRT2 has been shown to interact with:

α-tubulin,{{cite journal | vauthors = Yuan Q, Zhan L, Zhou QY, Zhang LL, Chen XM, Hu XM, Yuan XC | title = SIRT2 regulates microtubule stabilization in diabetic cardiomyopathy | journal = European Journal of Pharmacology | volume = 764 | pages = 554–561 | date = October 2015 | pmid = 26209361 | doi = 10.1016/j.ejphar.2015.07.045 }}
TUG,{{cite journal | vauthors = Belman JP, Bian RR, Habtemichael EN, Li DT, Jurczak MJ, Alcázar-Román A, McNally LJ, Shulman GI, Bogan JS | title = Acetylation of TUG protein promotes the accumulation of GLUT4 glucose transporters in an insulin-responsive intracellular compartment | journal = The Journal of Biological Chemistry | volume = 290 | issue = 7 | pages = 4447–4463 | date = February 2015 | pmid = 25561724 | pmc = 4326849 | doi = 10.1074/jbc.M114.603977 | doi-access = free }}
β-catenin,{{cite journal | vauthors = Nguyen P, Lee S, Lorang-Leins D, Trepel J, Smart DK | title = SIRT2 interacts with β-catenin to inhibit Wnt signaling output in response to radiation-induced stress | journal = Molecular Cancer Research | volume = 12 | issue = 9 | pages = 1244–1253 | date = September 2014 | pmid = 24866770 | pmc = 4163538 | doi = 10.1158/1541-7786.MCR-14-0223-T }}
PGAM2,{{cite journal | vauthors = Xu Y, Li F, Lv L, Li T, Zhou X, Deng CX, Guan KL, Lei QY, Xiong Y | title = Oxidative stress activates SIRT2 to deacetylate and stimulate phosphoglycerate mutase | journal = Cancer Research | volume = 74 | issue = 13 | pages = 3630–3642 | date = July 2014 | pmid = 24786789 | pmc = 4303242 | doi = 10.1158/0008-5472.CAN-13-3615 }}
TIAM1,{{cite journal | vauthors = Saxena M, Dykes SS, Malyarchuk S, Wang AE, Cardelli JA, Pruitt K | title = The sirtuins promote Dishevelled-1 scaffolding of TIAM1, Rac activation and cell migration | journal = Oncogene | volume = 34 | issue = 2 | pages = 188–198 | date = January 2015 | pmid = 24362520 | pmc = 4067478 | doi = 10.1038/onc.2013.549 }}
ApoE4,{{cite journal | vauthors = Theendakara V, Patent A, Peters Libeu CA, Philpot B, Flores S, Descamps O, Poksay KS, Zhang Q, Cailing G, Hart M, John V, Rao RV, Bredesen DE | title = Neuroprotective Sirtuin ratio reversed by ApoE4 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 45 | pages = 18303–18308 | date = November 2013 | pmid = 24145446 | pmc = 3831497 | doi = 10.1073/pnas.1314145110 | doi-access = free | bibcode = 2013PNAS..11018303T }}
p53,{{cite journal | vauthors = van Leeuwen IM, Higgins M, Campbell J, McCarthy AR, Sachweh MC, Navarro AM, Laín S | title = Modulation of p53 C-terminal acetylation by mdm2, p14ARF, and cytoplasmic SirT2 | journal = Molecular Cancer Therapeutics | volume = 12 | issue = 4 | pages = 471–480 | date = April 2013 | pmid = 23416275 | doi = 10.1158/1535-7163.MCT-12-0904 | doi-access = free }}
PEPCK,{{cite journal | vauthors = Jiang W, Wang S, Xiao M, Lin Y, Zhou L, Lei Q, Xiong Y, Guan KL, Zhao S | title = Acetylation regulates gluconeogenesis by promoting PEPCK1 degradation via recruiting the UBR5 ubiquitin ligase | journal = Molecular Cell | volume = 43 | issue = 1 | pages = 33–44 | date = July 2011 | pmid = 21726808 | pmc = 3962309 | doi = 10.1016/j.molcel.2011.04.028 }}
FOXO1,{{cite journal | vauthors = Wang F, Tong Q | title = SIRT2 suppresses adipocyte differentiation by deacetylating FOXO1 and enhancing FOXO1's repressive interaction with PPARgamma | journal = Molecular Biology of the Cell | volume = 20 | issue = 3 | pages = 801–808 | date = February 2009 | pmid = 19037106 | pmc = 2633403 | doi = 10.1091/mbc.E08-06-0647 }}
p300,{{cite journal | vauthors = Han Y, Jin YH, Kim YJ, Kang BY, Choi HJ, Kim DW, Yeo CY, Lee KY | title = Acetylation of Sirt2 by p300 attenuates its deacetylase activity | journal = Biochemical and Biophysical Research Communications | volume = 375 | issue = 4 | pages = 576–580 | date = October 2008 | pmid = 18722353 | doi = 10.1016/j.bbrc.2008.08.042 }}
14-3-3 protein,{{cite journal | vauthors = Jin YH, Kim YJ, Kim DW, Baek KH, Kang BY, Yeo CY, Lee KY | title = Sirt2 interacts with 14-3-3 beta/gamma and down-regulates the activity of p53 | journal = Biochemical and Biophysical Research Communications | volume = 368 | issue = 3 | pages = 690–695 | date = April 2008 | pmid = 18249187 | doi = 10.1016/j.bbrc.2008.01.114 }}
G6PD, and
CBP.{{cite journal | vauthors = Shimazu T, Horinouchi S, Yoshida M | title = Multiple histone deacetylases and the CREB-binding protein regulate pre-mRNA 3'-end processing | journal = The Journal of Biological Chemistry | volume = 282 | issue = 7 | pages = 4470–4478 | date = February 2007 | pmid = 17172643 | doi = 10.1074/jbc.M609745200 | doi-access = free }}

References

External links

{{PDBe-KB2|Q8IXJ6|NAD-dependent protein deacetylase sirtuin-2}}

Category:Genes mutated in mice