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.
Highlights
Hypoxia is a physiological stress that frequently occurs in solid tissues
We demonstrated that symmetrical dimethylation of Unc-51 like autophagy activating kinase 1 (ULK1) arginine (R)[170], which is governed by protein arginine methyltransferase 5 (PRMT5) and KDM5C, is sensitive to oxygen availability
To examine the effect of hypoxia on autophagy induction, we examined the levels of autophagy markers, Light Chain 3 (LC3) II and p62, in LN229 human glioblastoma (GBM) cells, Huh[7] hepatocellular carcinoma (HCC) cells, and human oral keratinocytes (HOKs) cultured in the hypoxic environment (1% oxygen)
Summary
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. Dimethylation of ULK1 promotes autophosphorylation at T180, a prerequisite for ULK1 activation, subsequently causing phosphorylation of Atg[13] and Beclin 1, autophagosome formation, mitochondrial clearance and reduced oxygen consumption. This study identifies an oxygen-sensitive methylation of ULK1 with an important role in hypoxic stress adaptation by promoting autophagy induction. Though HIF1α plays an important role in autophagy induction by releasing Beclin 1 from Bcl-222,23, the mechanisms underlying autophagy initiation under hypoxic stress remains unclear. We demonstrated that symmetrical dimethylation of ULK1 arginine (R)[170], which is governed by PRMT5 and KDM5C, is sensitive to oxygen availability. This modification of ULK1 promotes autophagosome formation and mitochondria clearance, and is required for cell adaptation to hypoxic stress
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