近日，国际著名杂志Science在线刊登了清华大学生命学院俞立教授课题组的最新研究成果“Function and molecular mechanism of acetylation in autophagy regulation，”，文章中，作者报道了组蛋白乙酰化酶Esa1以及去乙酰化酶Rpd3通过调节自噬发生关键蛋白Atg3的乙酰化水平，从而实现对自噬过程的动态调控。
细胞自噬(Autophagy)是一类在进化过程中高度保守的物质降解途径，目前发现自噬参与了蛋白质、脂质、受损细胞器和蛋白聚集体的降解。大量研究表明，细胞自噬在细胞存活、细胞死亡、抗原呈递、病原体的感染过程中发挥着重要作用。细胞自噬功能的异常与许多疾病的发生也有直接关系，如癌症，神经退行性疾病，免疫病等。因此，研究细胞自噬发生的分子机制对于这些疾病的治疗具有重要的指导意义。
俞立课题组以酿酒酵母为模式生物，通过遗传学筛选，发现乙酰化酶Esa1和去乙酰化酶Rpd3会调控自噬，作者进而利用遗传学和生化手段发现了自噬蛋白Atg3是Esa1和Rpd3的作用底物并用质谱鉴定了乙酰化位点。通过分析Atg3乙酰化位点突变体，作者发现乙酰化通过调节Atg3 和Atg8的相互作用而影响自吞噬。 此外，作者还发现Esa1在哺乳动物同源物Tip60同样影响了细胞自噬的发生，它的Atg3蛋白也被乙酰化修饰，证明了该机制是一种进化过程中上非常保守的机制。
值得一提的是，厦门大学生命学院林圣彩教授发现在生长因子缺失的情况下， Tip60能够乙酰化修饰自噬蛋白ULK1，从而调控自噬的发生，这一研究成果发表在同一期Science上。
清华大学生命学院09级博士生易聪是本文的第一作者，清华大学生命学院俞立教授是本文的通讯作者，邓海腾教授在Atg3蛋白的质谱分析方面做了大量的工作，南开大学医学院谢志平教授以及华中农业大学动物科技学院晏向华副教授等也参与了此项工作。（生物谷Bioon.com）
doi:10.1126/science.1216990
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Function and Molecular Mechanism of Acetylation in Autophagy Regulation
Cong Yi1, Meisheng Ma1, Leili Ran1, Jingxiang Zheng1, Jingjing Tong1, Jing Zhu1, Chengying Ma2, Yufen Sun1, Shaojin Zhang1, Wenzhi Feng1, Liyuan Zhu1, Yan Le1, Xingqi Gong2, Xianghua Yan3, Bing Hong4, Fen-Jun Jiang4, Zhiping Xie4, Di Miao5, Haiteng Deng5, Li Yu1,*
Protein acetylation emerged as a key regulatory mechanism for many cellular processes. We used genetic analysis of Saccharomyces cerevisiae to identify Esa1 as a histone acetyltransferase required for autophagy. We further identified the autophagy signaling component Atg3 as a substrate for Esa1. Specifically, acetylation of K19 and K48 of Atg3 regulated autophagy by controlling Atg3 and Atg8 interaction and lipidation of Atg8. Starvation induced transient K19-K48 acetylation through spatial and temporal regulation of the localization of acetylase Esa1 and the deacetylase Rpd3 on pre-autophagosomal structures (PASs) and their interaction with Atg3. Attenuation of K19-K48 acetylation was associated with attenuation of autophagy. Increased K19-K48 acetylation after deletion of the deacetylase Rpd3 caused increased autophagy. Thus, protein acetylation contributes to control of autophagy.
doi:10.1126/science.1217032
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GSK3-TIP60-ULK1 Signaling Pathway Links Growth Factor Deprivation to Autophagy
Shu-Yong Lin1,*, Terytty Yang Li1,*, Qing Liu1, Cixiong Zhang1, Xiaotong Li1, Yan Chen1, Shi-Meng Zhang2, Guili Lian1, Qi Liu1, Ka Ruan1, Zhen Wang1, Chen-Song Zhang1, Kun-Yi Chien3, Jiawei Wu4, Qinxi Li1, Jiahuai Han1, Sheng-Cai Lin1,†
In metazoans, cells depend on extracellular growth factors for energy homeostasis. We found that glycogen synthase kinase-3 (GSK3), when deinhibited by default in cells deprived of growth factors, activates acetyltransferase TIP60 through phosphorylating TIP60-Ser86, which directly acetylates and stimulates the protein kinase ULK1, which is required for autophagy. Cells engineered to express TIP60S86A that cannot be phosphorylated by GSK3 could not undergo serum deprivation–induced autophagy. An acetylation-defective mutant of ULK1 failed to rescue autophagy in ULK1−/− mouse embryonic fibroblasts. Cells used signaling from GSK3 to TIP60 and ULK1 to regulate autophagy when deprived of serum but not glucose. These findings uncover an activating pathway that integrates protein phosphorylation and acetylation to connect growth factor deprivation to autophagy.
