Autophagy is a conserved and tightly regulated intracellular quality control pathway. ULK is a key kinase in autophagy initiation, but whether ULK kinase activity also participates in the late stages of autophagy remains unknown. Here, we found that the autophagosomal SNARE protein, STX17, is phosphorylated by ULK at residue S289, beyond which it localizes specifically to autophagosomes. Inhibition of STX17 phosphorylation prevents such autophagosome localization. FLNA was then identified as a linker between ATG8 family proteins (ATG8s) and STX17 with essential involvement in STX17 recruitment to autophagosomes. Phosphorylation of STX17 S289 promotes its interaction with FLNA, activating its recruitment to autophagosomes and facilitating autophagosome–lysosome fusion. Disease-causative mutations around the ATG8s- and STX17-binding regions of FLNA disrupt its interactions with ATG8s and STX17, inhibiting STX17 recruitment and autophagosome–lysosome fusion. Cumulatively, our study reveals an unexpected role of ULK in autophagosome maturation, uncovers its regulatory mechanism in STX17 recruitment, and highlights a potential association between autophagy and FLNA.
ULK phosphorylation of STX17 controls autophagosome maturation via FLNA
Disclosures: The authors declare no competing interests exist.
- Award Id(s): ,92254302,91854116,31771529,321706852023BR028
Yufen Wang, Huilin Que, ChuangPeng Li, Zhe Wu, Fenglei Jian, Yuan Zhao, Haohao Tang, Yang Chen, Shuaixin Gao, Catherine C.L. Wong, Ying Li, Chongchong Zhao, Yueguang Rong; ULK phosphorylation of STX17 controls autophagosome maturation via FLNA. J Cell Biol 7 August 2023; 222 (8): e202211025. doi: https://doi.org/10.1083/jcb.202211025
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