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

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.