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), Sirt6 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.
Highlights
SIRT6 belongs to the Sir2 family of nicotinamide adenine dinucleotide (NAD+)-dependent protein lysine deacylases
We knocked down R-Ras2 in Sirt6 wild type (WT) and KO mouse embryonic fibroblasts (MEFs) and examined the cell proliferation
We found that the defatty-acylase activity of SIRT6 is important for regulating cell proliferation
Summary
SIRT6 (sirtuin 6) belongs to the Sir (silencing information regulator 2) family of nicotinamide adenine dinucleotide (NAD+)-dependent protein lysine deacylases. It plays important roles in a variety of biological processes, including DNA damage and repair (Kaidi et al, 2010; Mao et al, 2011; Toiber et al, 2013), glucose metabolism (Zhong et al, 2010), and cell proliferation (Sebastian et al, 2012). Lysine fatty acylation promotes TNFa targeting to lysosome and decreases its secretion (Jiang et al, 2016) It remains unclear whether SIRT6 regulates other proteins by defatty-acylation
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