自噬相关蛋白ATG4B是哺乳类细胞自噬调节的关键蛋白，其与肝细胞癌（HCC）密切相关。乙酰化/去乙酰化修饰是蛋白质活性调节的重要方式，但其是否参与调节ATG4B的活性，目前尚未见报道。我们通过前期探索，证实ATG4B活性（而非其蛋白水平）的升高促进了饥饿条件下HCC细胞的自噬与存活，进而首次发现乙酰化水平的变化可能是调节ATG4B活性的重要因素。据此提出如下假设：赖氨酸乙酰转移酶可能通过催化ATG4B的乙酰化修饰而降低ATG4B的活性，从而抑制HCC细胞的自噬与存活；而去乙酰化酶SIRT1诱导的ATG4B去乙酰化则可能通过升高ATG4B的活性而促进HCC细胞的自噬与存活。本项目将围绕该假设开展一系列研究，以期率先揭示乙酰化/去乙酰化修饰调控ATG4B活性的具体分子机制，明确相关机制是影响HCC细胞自噬与存活的重要方式，为探索和设计以ATG4B及其乙酰化/去乙酰化修饰为靶标的抗HCC新策略提供科学依据。

Autophagy related 4B (ATG4B) is a key protein in the regulation of autophagy in mammalian cells, and it is closely related with hepatocellular carcinoma (HCC). Acetylation/deacetylation plays important roles in regulating the activities of proteins. However, it is unknown at present whether acetylation/deacetylation is involved in the regulation of ATG4B activity. Our pilot investigation demonstrated that the elevation of ATG4B activity (but not its protein level) promoted the autophagy and survival of HCC cells under starvation. Furthermore, we for the first time showed that the change of acetylation level may be an essential factor for manipulating ATG4B activity. Based on the innovative findings, we hypothesize that lysine acetyltransferase may decrease the activity of ATG4B and suppress the autophagy and survival of HCC cells by catalyzing ATG4B acetylation, while the deacetylase SIRT1-induced deacetylation of ATG4B may enhance the autophagy and survival of HCC cells through increasing ATG4B activity. In the present project, we will carry out a series of studies around this hypothesis in order to illustrate the detailed molecular mechanisms by which acetylation/deacetylation regulates ATG4B activity. Furthermore, we will clarify that the above molecular mechanisms are important ways to influence the autophagy and survival of HCC cells. The expected results of this project may provide scientific evidences for exploring and designing novel anti-HCC strategies by targeting ATG4B and its acetylation/deacetylation.