自噬相关蛋白ATG16L1的翻译后修饰调控缺氧/复氧后心肌细胞凋亡的机制研究

自噬上调能有效抑制心肌细胞在急性缺氧条件下的凋亡。我们研究发现自噬相关蛋白ATG16L1的磷酸化修饰能够促进心肌细胞在缺氧时的自噬,抑制了心肌细胞在急性缺氧条件下的凋亡。但自噬相关蛋白的精氨酸甲基化修饰也能调节其功能，从而保护心肌细胞。本课题的实验计划是：1、自噬相关蛋白ATG16L1是否有精氨酸甲基化修饰。2、这种甲基化修饰的水平是否受心肌细胞缺氧/复氧调控。3、通过质谱分析鉴定哪些甲基转移酶和脱甲基酶介导了这种修饰。4、探讨这些甲基转移酶和脱甲基酶的小分子抑制子或激活化合物是否能抑制心肌细胞在急性缺氧条件下的凋亡。这两种翻译后修饰共同在心肌细胞缺氧/复氧时发挥调控作用，因此对自噬相关蛋白翻译后修饰的研究有望进一步阐明自噬的分子机制，从而为心梗治疗提供新的治疗靶点。

Autophagy upregulation can efficiently inhibit the apoptosis of cardiomyocytes during hypoxia/reoxygenation (H/R). We previously reported that the phosphorylation and lysine methylation of ATG16L1 can promote the autophagy of cardiomyocytes during H/R, which inhibits the apoptosis of cardiomyocytes during H/R. However, very little was known about the role of the arginine methylation modification of autophagy-related protein in the autophagy and apoptosis of cardiomyocytes. In this project, we are aimed to answer the following questions. 1) Does the arginine methylation modification happen in key autophagy-related protein ATG16L1? 2)Does H/R regulate the arginine methylation modification of autophagy-related proteins? 3) By using tandem mass spectra, we want to identify which of the arginine methyltransferases and demethylases to mediate this kind of modification? 4) By using the small molecular inhibitor or activator, we want to examine whether they can inhibit the apoptosis of cardiomyocytes during H/R. Based on our preliminary data and literatures, we reasoned that these modifications play roles in the cardiomyocytes during H/R. Therefore, the study on the post-translational modifications of autophagy-related proteins will help to further elucidate the molecular mechanism on autophagy, which will provide novel treatment option for infarct therapy.