From the Life Sciences Institute.
J Biol Chem. 2014 May 9;289(19):13132-41. doi: 10.1074/jbc.M113.520734. Epub 2014 Mar 20.
p70 ribosomal S6 kinase (S6K1), a major substrate of the mammalian target of rapamycin (mTOR) kinase, regulates diverse cellular processes including protein synthesis, cell growth, and survival. Although it is well known that the activity of S6K1 is tightly coupled to its phosphorylation status, the regulation of S6K1 activity by other post-translational modifications such as acetylation has not been well understood. Here we show that the acetylation of the C-terminal region (CTR) of S6K1 blocks mTORC1-dependent Thr-389 phosphorylation, an essential phosphorylation site for S6K1 activity. The acetylation of the CTR of S6K1 is inhibited by the class III histone deacetylases, SIRT1 and SIRT2. An S6K1 mutant lacking acetylation sites in its CTR shows enhanced Thr-389 phosphorylation and kinase activity, whereas the acetylation-mimetic S6K1 mutant exhibits decreased Thr-389 phosphorylation and kinase activity. Interestingly, relative to the acetylation-mimetic S6K1 mutant, the acetylation-defective mutant displays higher affinity toward Raptor, an essential scaffolding component of mTORC1 that recruits mTORC1 substrates. These observations indicate that sirtuin-mediated regulation of S6K1 acetylation is an additional important regulatory modification that impinges on the mechanisms underlying mTORC1-dependent S6K1 activation.
p70 核糖体 S6 激酶（S6K1）是哺乳动物雷帕霉素靶蛋白（mTOR）激酶的主要底物，调节多种细胞过程，包括蛋白质合成、细胞生长和存活。尽管众所周知，S6K1 的活性与其磷酸化状态紧密相关，但 S6K1 活性的其他翻译后修饰（如乙酰化）的调节尚未得到很好的理解。在这里，我们表明 S6K1 的 C 端区域（CTR）的乙酰化阻止了 mTORC1 依赖性 Thr-389 磷酸化，这是 S6K1 活性的一个必需磷酸化位点。S6K1 的 CTR 的乙酰化受第三类组蛋白去乙酰化酶 SIRT1 和 SIRT2 抑制。缺乏 CTR 中乙酰化位点的 S6K1 突变体显示增强的 Thr-389 磷酸化和激酶活性，而乙酰化模拟 S6K1 突变体则显示出降低的 Thr-389 磷酸化和激酶活性。有趣的是，与乙酰化模拟 S6K1 突变体相比，乙酰化缺陷突变体与 Raptor（mTORC1 的必需支架成分，募集 mTORC1 底物）具有更高的亲和力。这些观察结果表明，Sirtuin 介导的 S6K1 乙酰化调节是影响 mTORC1 依赖性 S6K1 激活机制的另一个重要调节修饰。
