Regulation of mATG9 trafficking by Src- and ULK1-mediated phosphorylation in basal and starvation-induced autophagy

• Published in: Cell research Vol. 27; no. 2; pp. 184 - 201
• Main Authors: Zhou, Changqian, Ma, Kaili, Gao, Ruize, Mu, Chenglong, Chen, Linbo, Liu, Qiangqiang, Luo, Qian, Feng, Du, Zhu, Yushan, Chen, Quan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2017; Nature Publishing Group
• Subjects: 631/80/313; 631/80/458/1733; 631/80/82/39; 631/80/86; Amino Acid Sequence; Autophagy - drug effects; Autophagy-Related Protein-1 Homolog - metabolism; Autophagy-Related Proteins - chemistry; Autophagy-Related Proteins - metabolism; Biomedical and Life Sciences; Cell Biology; Cell Membrane - metabolism; Conserved Sequence; Epidermal Growth Factor - pharmacology; HEK293 Cells; HeLa Cells; Humans; Intracellular Signaling Peptides and Proteins - metabolism; Life Sciences; Membrane Proteins - chemistry; Membrane Proteins - metabolism; Membranes; Original; original-article; Phosphorylation - drug effects; Phosphotyrosine - metabolism; Protein Transport - drug effects; src-Family Kinases - metabolism; Starvation - metabolism; Starvation - pathology; Stress, Physiological - drug effects; Vesicular Transport Proteins - chemistry; Vesicular Transport Proteins - metabolism; Src kinase; ULK1 kinase; autophagy; mATG9 trafficking; basal autophagy
• ISSN: 1001-0602; 1748-7838; 1748-7838
• DOI: 10.1038/cr.2016.146

Autophagy requires diverse membrane sources and involves membrane trafficking of mATG9, the only membrane protein in the ATG family. However, the molecular regulation of mATG9 trafficking for autophagy initiation remains unclear. Here we identified two conserved classic adaptor protein sorting signals within the cytosolic N-terminus of mATG9, which mediate trafficking of mATG9 from the plasma membrane and trans-Golgi network (TGN) via interaction with the AP1/2 complex. Src phosphorylates mATG9 at Tyr8 to maintain its endocytic and constitutive trafficking in unstressed conditions. In response to starvation, phosphorylation of mATG9 at Tyr8 by Src and at Ser14 by ULK1 functionally cooperate to promote interactions between mATG9 and the AP1/2 complex, leading to redistribution of mATG9 from the plasma membrane and juxta-nuclear region to the peripheral pool for autophagy initiation. Our findings uncover novel mechanisms of mATG9 trafficking and suggest a coordination of basal and stress-induced autophagy.