SIRT2 and lysine fatty acylation regulate the transforming activity of K-Ras4a.
SIRT2 and lysine fatty acylation regulate the transforming activity of K-Ras4a.
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作者：
Jing H;Zhang X;Wisner SA;Chen X;Spiegelman NA;Linder ME;Lin H
Ras蛋白在许多生物过程中起着至关重要的作用，在许多人类肿瘤中发现了Ras突变。了解Ras蛋白是如何调控的，对于阐明细胞信号通路和确定治疗人类疾病的新靶点具有重要意义。在这里，我们报道了K-Ras剪接变体之一K-Ras4a受赖氨酸脂肪酰化的影响，这是一种先前研究不足的蛋白质翻译后修饰。Sirtuin 2 （SIRT2）是哺乳动物烟酰胺腺嘌呤二核苷酸（NAD）依赖赖氨酸脱乙酰酶之一，可催化K-Ras4a中脂肪酰化的去除。我们进一步证明sirt2介导的赖氨酸酰化促进K-Ras4a的膜定位，增强其与A-Raf的相互作用，从而促进细胞转化。我们的研究确定赖氨酸脂肪酰化是一种以前未知的Ras家族GTPases的调节机制，与半胱氨酸脂肪酰化不同。这些发现突出了赖氨酸脂肪酰化和sirtuin催化的蛋白质赖氨酸脂肪酰化的生物学意义。
Ras proteins play vital roles in numerous biological processes and Ras mutations are found in many human tumors. Understanding how Ras proteins are regulated is important for elucidating cell signaling pathways and identifying new targets for treating human diseases. Here we report that one of the K-Ras splice variants, K-Ras4a, is subject to lysine fatty acylation, a previously under-studied protein post-translational modification. Sirtuin 2 (SIRT2), one of the mammalian nicotinamide adenine dinucleotide (NAD)-dependent lysine deacylases, catalyzes the removal of fatty acylation from K-Ras4a. We further demonstrate that SIRT2-mediated lysine defatty-acylation promotes endomembrane localization of K-Ras4a, enhances its interaction with A-Raf, and thus promotes cellular transformation. Our study identifies lysine fatty acylation as a previously unknown regulatory mechanism for the Ras family of GTPases that is distinct from cysteine fatty acylation. These findings highlight the biological significance of lysine fatty acylation and sirtuin-catalyzed protein lysine defatty-acylation.