近日,，國(guó)際著名雜志Science在線刊登了清華大學(xué)生命學(xué)院俞立教授課題組的最新研究成果“Function and molecular mechanism of acetylation in autophagy regulation,，”,，文章中，作者報(bào)道了組蛋白乙酰化酶Esa1以及去乙?；窻pd3通過(guò)調(diào)節(jié)自噬發(fā)生關(guān)鍵蛋白Atg3的乙?；剑瑥亩鴮?shí)現(xiàn)對(duì)自噬過(guò)程的動(dòng)態(tài)調(diào)控,。
細(xì)胞自噬(Autophagy)是一類(lèi)在進(jìn)化過(guò)程中高度保守的物質(zhì)降解途徑,，目前發(fā)現(xiàn)自噬參與了蛋白質(zhì)、脂質(zhì),、受損細(xì)胞器和蛋白聚集體的降解,。大量研究表明，細(xì)胞自噬在細(xì)胞存活,、細(xì)胞死亡,、抗原呈遞、病原體的感染過(guò)程中發(fā)揮著重要作用,。細(xì)胞自噬功能的異常與許多疾病的發(fā)生也有直接關(guān)系,，如癌癥，神經(jīng)退行性疾病,，免疫病等,。因此，研究細(xì)胞自噬發(fā)生的分子機(jī)制對(duì)于這些疾病的治療具有重要的指導(dǎo)意義,。
俞立課題組以釀酒酵母為模式生物,，通過(guò)遺傳學(xué)篩選,，發(fā)現(xiàn)乙?；窫sa1和去乙酰化酶Rpd3會(huì)調(diào)控自噬,，作者進(jìn)而利用遺傳學(xué)和生化手段發(fā)現(xiàn)了自噬蛋白Atg3是Esa1和Rpd3的作用底物并用質(zhì)譜鑒定了乙?；稽c(diǎn)。通過(guò)分析Atg3乙?；稽c(diǎn)突變體,，作者發(fā)現(xiàn)乙酰化通過(guò)調(diào)節(jié)Atg3 和Atg8的相互作用而影響自吞噬,。 此外,，作者還發(fā)現(xiàn)Esa1在哺乳動(dòng)物同源物Tip60同樣影響了細(xì)胞自噬的發(fā)生，它的Atg3蛋白也被乙?；揎?，證明了該機(jī)制是一種進(jìn)化過(guò)程中上非常保守的機(jī)制。
值得一提的是,，廈門(mén)大學(xué)生命學(xué)院林圣彩教授發(fā)現(xiàn)在生長(zhǎng)因子缺失的情況下,， Tip60能夠乙酰化修飾自噬蛋白ULK1，從而調(diào)控自噬的發(fā)生,，這一研究成果發(fā)表在同一期Science上,。
清華大學(xué)生命學(xué)院09級(jí)博士生易聰是本文的第一作者，清華大學(xué)生命學(xué)院俞立教授是本文的通訊作者,，鄧海騰教授在Atg3蛋白的質(zhì)譜分析方面做了大量的工作,，南開(kāi)大學(xué)醫(yī)學(xué)院謝志平教授以及華中農(nóng)業(yè)大學(xué)動(dòng)物科技學(xué)院晏向華副教授等也參與了此項(xiàng)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.
