SIRT6 Regulates Ras-related Protein R-Ras2 by Lysine Defatty-acylation

Overview

Journal Elife

Specialty Biology

Date 2017 Apr 14

PMID 28406396

Citations 46

Authors

Xiaoyu Zhang

Nicole A Spiegelman

Ornella D Nelson

Hui Jing

Hening Lin

Affiliations

Soon will be listed here.

Abstract

The Ras family of GTPases are important in cell signaling and frequently mutated in human tumors. Understanding their regulation is thus important for studying biology and human diseases. Here, we report that a novel posttranslational mechanism, reversible lysine fatty acylation, regulates R-Ras2, a member of the Ras family. SIRT6, a sirtuin with established tumor suppressor function, regulates the lysine fatty acylation of R-Ras2. In mouse embryonic fibroblasts (MEFs), knockout (KO) increased R-Ras2 lysine fatty acylation. Lysine fatty acylation promotes the plasma membrane localization of R-Ras2 and its interaction with phosphatidylinositol 3-kinase PI3K, leading to activated Akt and increased cell proliferation. Our study establishes lysine fatty acylation as a previously unknown mechanism that regulates the Ras family of GTPases and provides an important mechanism by which SIRT6 functions as a tumor suppressor.

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References

Michishita E, McCord R, Boxer L, Barber M, Hong T, Gozani O . Cell cycle-dependent deacetylation of telomeric histone H3 lysine K56 by human SIRT6. Cell Cycle. 2009; 8(16):2664-6. PMC: 4474138. DOI: 10.4161/cc.8.16.9367. View

Mao Z, Hine C, Tian X, Van Meter M, Au M, Vaidya A . SIRT6 promotes DNA repair under stress by activating PARP1. Science. 2011; 332(6036):1443-6. PMC: 5472447. DOI: 10.1126/science.1202723. View

Yang B, Zwaans B, Eckersdorff M, Lombard D . The sirtuin SIRT6 deacetylates H3 K56Ac in vivo to promote genomic stability. Cell Cycle. 2009; 8(16):2662-3. PMC: 2728171. DOI: 10.4161/cc.8.16.9329. View

Mostoslavsky R, Chua K, Lombard D, Pang W, Fischer M, Gellon L . Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell. 2006; 124(2):315-29. DOI: 10.1016/j.cell.2005.11.044. View

Cox A, Fesik S, Kimmelman A, Luo J, Der C . Drugging the undruggable RAS: Mission possible?. Nat Rev Drug Discov. 2014; 13(11):828-51. PMC: 4355017. DOI: 10.1038/nrd4389. View

Murphy G, Graham S, Morita S, Reks S, Vojtek A, Kelley G . Involvement of phosphatidylinositol 3-kinase, but not RalGDS, in TC21/R-Ras2-mediated transformation. J Biol Chem. 2002; 277(12):9966-75. DOI: 10.1074/jbc.M109059200. View

Du J, Zhou Y, Su X, Yu J, Khan S, Jiang H . Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase. Science. 2011; 334(6057):806-9. PMC: 3217313. DOI: 10.1126/science.1207861. View

Rosario M, PATERSON H, Marshall C . Activation of the Ral and phosphatidylinositol 3' kinase signaling pathways by the ras-related protein TC21. Mol Cell Biol. 2001; 21(11):3750-62. PMC: 87018. DOI: 10.1128/MCB.21.11.3750-3762.2001. View

Michishita E, McCord R, Berber E, Kioi M, Padilla-Nash H, Damian M . SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin. Nature. 2008; 452(7186):492-6. PMC: 2646112. DOI: 10.1038/nature06736. View

10.

Kaidi A, Weinert B, Choudhary C, Jackson S . RETRACTED: Human SIRT6 promotes DNA end resection through CtIP deacetylation. Science. 2010; 329(5997):1348-53. PMC: 3276839. DOI: 10.1126/science.1192049. View

11.

He B, Hu J, Zhang X, Lin H . Thiomyristoyl peptides as cell-permeable Sirt6 inhibitors. Org Biomol Chem. 2014; 12(38):7498-502. PMC: 4161628. DOI: 10.1039/c4ob00860j. View

12.

Sundaresan N, Vasudevan P, Zhong L, Kim G, Samant S, Parekh V . The sirtuin SIRT6 blocks IGF-Akt signaling and development of cardiac hypertrophy by targeting c-Jun. Nat Med. 2012; 18(11):1643-50. PMC: 4401084. DOI: 10.1038/nm.2961. View

13.

Liszt G, Ford E, Kurtev M, Guarente L . Mouse Sir2 homolog SIRT6 is a nuclear ADP-ribosyltransferase. J Biol Chem. 2005; 280(22):21313-20. DOI: 10.1074/jbc.M413296200. View

14.

Lee J, Pyon J, Lee S, Lee Y, Kang S, Kim C . Greater expression of TC21/R-ras2 in highly aggressive malignant skin cancer. Int J Dermatol. 2011; 50(8):956-60. DOI: 10.1111/j.1365-4632.2010.04846.x. View

15.

Wennerberg K, Rossman K, Der C . The Ras superfamily at a glance. J Cell Sci. 2005; 118(Pt 5):843-6. DOI: 10.1242/jcs.01660. View

16.

Ahearn I, Haigis K, Bar-Sagi D, Philips M . Regulating the regulator: post-translational modification of RAS. Nat Rev Mol Cell Biol. 2011; 13(1):39-51. PMC: 3879958. DOI: 10.1038/nrm3255. View

17.

Toiber D, Erdel F, Bouazoune K, Silberman D, Zhong L, Mulligan P . SIRT6 recruits SNF2H to DNA break sites, preventing genomic instability through chromatin remodeling. Mol Cell. 2013; 51(4):454-68. PMC: 3761390. DOI: 10.1016/j.molcel.2013.06.018. View

18.

Charron G, Zhang M, Yount J, Wilson J, Raghavan A, Shamir E . Robust fluorescent detection of protein fatty-acylation with chemical reporters. J Am Chem Soc. 2009; 131(13):4967-75. DOI: 10.1021/ja810122f. View

19.

Zhang X, Khan S, Jiang H, Antonyak M, Chen X, Spiegelman N . Identifying the functional contribution of the defatty-acylase activity of SIRT6. Nat Chem Biol. 2016; 12(8):614-20. PMC: 4955683. DOI: 10.1038/nchembio.2106. View

20.

Jiang H, Zhang X, Lin H . Lysine fatty acylation promotes lysosomal targeting of TNF-α. Sci Rep. 2016; 6:24371. PMC: 4832147. DOI: 10.1038/srep24371. View