Oxygen-sensitive methylation of ULK1 is required for hypoxia-induced autophagy

Jingyi Li, Tao Zhang, Tao Ren, Xiaoyu Liao, Yilong Hao, Je Sun Lim, Jong-Ho Lee, Mi Li, Jichun Shao and Rui Liu ()
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Jingyi Li: The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital
Tao Zhang: The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital
Tao Ren: Oncology Department, Clinical Medical College and The First Affiliated Hospital of Chengdu Medical College
Xiaoyu Liao: Sichuan University
Yilong Hao: Zhejiang University School of Medicine, and Key Laboratory of Oral Biomedical Research of Zhejiang Province, Clinical Research Center of Oral Diseases of Zhejiang Province
Je Sun Lim: The Graduate School of Dong-A University
Jong-Ho Lee: The Graduate School of Dong-A University
Mi Li: MD Anderson UTHealth Graduate School of Biomedical Sciences
Jichun Shao: The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital
Rui Liu: Sichuan University

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: Abstract Hypoxia is a physiological stress that frequently occurs in solid tissues. Autophagy, a ubiquitous degradation/recycling system in eukaryotic cells, renders cells tolerant to multiple stressors. However, the mechanisms underlying autophagy initiation upon hypoxia remains unclear. Here we show that protein arginine methyltransferase 5 (PRMT5) catalyzes symmetrical dimethylation of the autophagy initiation protein ULK1 at arginine 170 (R170me2s), a modification removed by lysine demethylase 5C (KDM5C). Despite unchanged PRMT5-mediated methylation, low oxygen levels decrease KDM5C activity and cause accumulation of ULK1 R170me2s. Dimethylation of ULK1 promotes autophosphorylation at T180, a prerequisite for ULK1 activation, subsequently causing phosphorylation of Atg13 and Beclin 1, autophagosome formation, mitochondrial clearance and reduced oxygen consumption. Further, expression of a ULK1 R170K mutant impaired cell proliferation under hypoxia. This study identifies an oxygen-sensitive methylation of ULK1 with an important role in hypoxic stress adaptation by promoting autophagy induction.

Date: 2022
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DOI: 10.1038/s41467-022-28831-6

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