State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Responses, Tianjin Key Laboratory of Protein Science, Haihe Laboratory of Cell Ecosystem, College of Life Sciences, Nankai University, Tianjin, China.
Key Laboratory of Weak-Light Nonlinear Photonics, Ministry of Education, School of Physics and TEDA Institute of Applied Physics, Nankai University, Tianjin 300071, China.
Cell Rep. 2022 Aug 16;40(7):111195. doi: 10.1016/j.celrep.2022.111195.
ATG9A is a highly conserved membrane protein required for autophagy initiation. It is trafficked from the trans-Golgi network (TGN) to the phagophore to act as a membrane source for autophagosome expansion. Here, we show that ATG9A is not just a passenger protein in the TGN but rather works in concert with GRASP55, a stacking factor for Golgi structure, to organize Golgi dynamics and integrity. Upon heat stress, the E3 ubiquitin ligase MARCH9 is promoted to ubiquitinate ATG9A in the form of K63 conjugation, and the nondegradable ubiquitinated ATG9A disperses from the Golgi apparatus to the cytoplasm more intensely, accompanied by inhibiting GRASP55 oligomerization, further resulting in Golgi fragmentation. Knockout of ATG9A or MARCH9 largely prevents Golgi fragmentation and protects Golgi functions under heat and other Golgi stresses. Our results reveal a noncanonical function of ATG9A for Golgi dynamics and suggest the pathway for sensing Golgi stress via the MARCH9/ATG9A axis.
ATG9A 是一种高度保守的膜蛋白，对于自噬的起始是必需的。它从高尔基体中转位到吞噬体，作为自噬体扩张的膜源。在这里，我们表明 ATG9A 不仅是 TGN 中的过客蛋白，而是与 GRASP55（高尔基体结构的堆积因子）协同作用，以组织高尔基体的动力学和完整性。在热应激下，E3 泛素连接酶 MARCH9 被促进以 K63 连接的形式泛素化 ATG9A，不可降解的泛素化 ATG9A 从高尔基体更强烈地分散到细胞质中，同时抑制 GRASP55 寡聚化，进一步导致高尔基体碎片化。ATG9A 或 MARCH9 的敲除在很大程度上防止了高尔基体的碎片化，并在热和其他高尔基体应激下保护了高尔基体的功能。我们的结果揭示了 ATG9A 用于高尔基体动力学的非典型功能，并提示了通过 MARCH9/ATG9A 轴感知高尔基体应激的途径。
