Function and molecular mechanism of N-terminal acetylation in autophagy
Function and molecular mechanism of N-terminal acetylation in autophagy
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N端乙酰化在自噬中的功能和分子机制
DOI：
10.1016/j.celrep.2021.109937
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发表时间：
2021-11-16
期刊：
影响因子：
8.8
通讯作者：
Lu，Kefeng
中科院分区：
文献类型：
--
作者：
Shen，Tianyun;Jiang，Lan;Lu，Kefeng
蛋白质中氨基酸的乙酰基连接是一种重要的翻译后修饰。然而，与赖氨酸乙酰化相比，N-末端乙酰化在细胞功能方面是难以捉摸的。在这里，我们确定Nat3是一种N端乙酰转移酶，对于自噬是必不可少的，这是一条大量运输和降解细胞质成分的分解代谢途径。我们确定肌动蛋白细胞骨架成分Act1和动力蛋白样GTPase Vps1(空泡蛋白分类1)是Nat3介导的第一个蛋氨酸N-末端乙酰化的底物。乙酰化的Act1形成肌动蛋白细丝，从而促进Atg9小泡的运输，以形成自噬小体；乙酰化的Vps1招募并促进SNARE(可溶性N-乙基马来酰亚胺敏感因子激活蛋白受体)复合体的捆绑，用于自噬小体与空泡的融合。ACT1和Vps1的N-末端乙酰化的取消与自噬过程的上游和下游步骤的阻断有关。因此，我们的工作表明，蛋白质N-末端乙酰化通过微调过程中的多个步骤，在控制自噬过程中发挥着关键作用。
Acetyl ligation to the amino acids in a protein is an important posttranslational modification. However, in contrast to lysine acetylation, N-terminal acetylation is elusive in terms of its cellular functions. Here, we identify Nat3 as an N-terminal acetyltransferase essential for autophagy, a catabolic pathway for bulk transport and degradation of cytoplasmic components. We identify the actin cytoskeleton constituent Act1 and dynamin-like GTPase Vps1 (vacuolar protein sorting 1) as substrates for Nat3-mediated N-terminal acetylation of the first methionine. Acetylated Act1 forms actin filaments and therefore promotes the transport of Atg9 vesicles for autophagosome formation; acetylated Vps1 recruits and facilitates bundling of the SNARE (soluble N-ethylmaleimide-sensitive factor activating protein receptor) complex for autophagosome fusion with vacuoles. Abolishment of the N-terminal acetylation of Act1 and Vps1 is associated with blockage of upstream and downstream steps of the autophagy process. Therefore, our work shows that protein N-terminal acetylation plays a critical role in controlling autophagy by fine-tuning multiple steps in the process.