Involvement of acetylation of ATG4B in controlling autophagy induction
Involvement of acetylation of ATG4B in controlling autophagy induction
复制标题
ATG4B 乙酰化参与控制自噬诱导
DOI：
10.1080/15548627.2022.2117887
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发表时间：
2022-09
期刊：
影响因子：
13.3
通讯作者：
Fengtian He
中科院分区：
文献类型：
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作者：
Haojun Xiong;Liangbo Sun;Jiqin Lian;Fengtian He
摘要ATG 4 B是一种半胱氨酸蛋白酶，通过可逆修饰Atg 8家族蛋白促进自噬体的形成，在控制应激反应中的大自噬/自噬启动中起着至关重要的作用。然而，ATG 4 B活性调节的分子机制远未得到很好的阐明。在本研究中，我们首次发现ATG 4 B在赖氨酸残基39（K39）的乙酰化水平强烈参与调节其活性和自噬。具体而言，SIRT 2使ATG 4 B K39脱乙酰，增强ATG 4 B活性和自噬通量，这可以被EP 300/p300拮抗。饥饿处理有助于EP 300抑制和SIRT 2激活，促进ATG 4 B K39的脱乙酰化，这导致ATG 4 B活性升高并最终启动自噬。机制研究表明，饥饿降低CCNE（细胞周期蛋白E），导致CCNE-CDK 2蛋白复合物的下调，降低SIRT 2 Ser 331的磷酸化，最终激活SIRT 2。此外，我们使用sirt 2基因敲除（sirt 2 −/−）小鼠证实，SIRT 2通过抑制K39处ATG 4 B的乙酰化来促进自噬。总的来说，我们的研究结果揭示了乙酰化介导的调节ATG 4 B半胱氨酸蛋白酶活性的自噬启动响应营养缺乏。
ABSTRACT ATG4B, a cysteine protease promoting autophagosome formation by reversibly modifying Atg8-family proteins, plays a vital role in controlling macroautophagy/autophagy initiation in response to stress. However, the molecular mechanism underlying the regulation of ATG4B activity is far from well elucidated. In the current study, we firstly revealed that the acetylation level of ATG4B at lysine residue 39 (K39) is strongly involved in regulating its activity and autophagy. Specifically, SIRT2 deacetylates ATG4B K39, enhancing ATG4B activity and autophagic flux, which can be antagonized by EP300/p300. Starvation treatment contributes to EP300 suppression and SIRT2 activation, promoting the deacetylation of ATG4B K39, which leads to the elevation of ATG4B activity and finally autophagy initiation. Mechanistic investigation showed that starvation reduces CCNE (cyclin E), resulting in the downregulation of the CCNE-CDK2 protein complex, decreasing the phosphorylation of SIRT2 Ser331 and finally activating SIRT2. In addition, we confirmed that SIRT2 promotes autophagy via suppressing acetylation of ATG4B at K39 using sirt2 gene knockout (sirt2 −/−) mice. Collectively, our results have revealed the acetylation-mediated regulation of ATG4B cysteine protease activity in autophagy initiation in response to nutritional deficiency.
ATG4B 去乙酰化促进饥饿条件下自噬的启动
影响因子：
13.6
作者：
通讯作者：
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