Cell Rep . 2022 Aug 16;40(7)(IF:9.995).

Nondegradable ubiquitinated ATG9A organizes Golgi integrity and dynamics upon stresses

Qian Luo 1Qiangqiang Liu 1Hongcheng Cheng 1Jiale Wang 1Tian Zhao 1Jiaojiao Zhang 1Chenglong Mu 1Yuanyuan Meng 1Linbo Chen 1Changqian Zhou 1Hong Lei 1Jianyu Yang 2Guo Chen 1Yanjun Li 1Leiting Pan 2Quan Chen 3Yushan Zhu 4

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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.

Keywords: ATG9A; CP: Molecular biology; Golgi dynamics; Golgi stress response; ubiquitination.