BK21 FOUR KNU Creative BioResearch Group, School of Life Sciences, Kyungpook National University, Daegu 41566, Korea.
Cells. 2022 Apr 13;11(8):1330. doi: 10.3390/cells11081330.
Autophagy plays a key role in eliminating and recycling cellular components in response to stress, including starvation. Dysregulation of autophagy is observed in various diseases, including neurodegenerative diseases, cancer, and diabetes. Autophagy is tightly regulated by autophagy-related (ATG) proteins. Autophagy-related 4 (ATG4) is the sole cysteine protease, and four homologs (ATG4A-D) have been identified in mammals. These proteins have two domains: catalytic and short fingers. ATG4 facilitates autophagy by promoting autophagosome maturation through reversible lipidation and delipidation of seven autophagy-related 8 (ATG8) homologs, including microtubule-associated protein 1-light chain 3 (LC3) and GABA type A receptor-associated protein (GABARAP). Each ATG4 homolog shows a preference for a specific ATG8 homolog. Post-translational modifications of ATG4, including phosphorylation/dephosphorylation, -GlcNAcylation, oxidation, S-nitrosylation, ubiquitination, and proteolytic cleavage, regulate its activity and ATG8 processing, thus modulating its autophagic activity. We reviewed recent advances in our understanding of the effect of post-translational modification on the regulation, activity, and function of ATG4, the main protease that controls autophagy.
自噬在响应压力（包括饥饿）时消除和回收细胞成分方面起着关键作用。自噬的失调在各种疾病中都有观察到，包括神经退行性疾病、癌症和糖尿病。自噬受到自噬相关（ATG）蛋白的严密调控。ATG4 是唯一的半胱氨酸蛋白酶，在哺乳动物中已鉴定出四个同源物（ATG4A-D）。这些蛋白质有两个结构域：催化结构域和短指结构域。ATG4 通过促进 7 种自噬相关 8（ATG8）同源物（包括微管相关蛋白 1-轻链 3（LC3）和 GABA A 受体相关蛋白（GABARAP））的自噬体成熟，来促进自噬，这些同源物通过可逆的脂质化和去脂化作用。每个 ATG4 同源物都表现出对特定 ATG8 同源物的偏好。ATG4 的翻译后修饰，包括磷酸化/去磷酸化、-GlcNAc 化、氧化、S-亚硝基化、泛素化和蛋白水解切割，调节其活性和 ATG8 加工，从而调节其自噬活性。我们综述了最近在理解翻译后修饰对调节、活性和功能的影响方面的进展，ATG4 是控制自噬的主要蛋白酶。
