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

Author

Listed:
  • Jingyi Li

    (The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital
    School of Biological Sciences and Technology, Chengdu Medical College)

  • Tao Zhang

    (The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital
    School of Biological Sciences and Technology, Chengdu Medical College)

  • 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
    Dong-A University)

  • Mi Li

    (MD Anderson UTHealth Graduate School of Biomedical Sciences
    The University of Texas MD Anderson Cancer Center)

  • Jichun Shao

    (The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital)

  • Rui Liu

    (Sichuan University)

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.

Suggested Citation

  • Jingyi Li & Tao Zhang & Tao Ren & Xiaoyu Liao & Yilong Hao & Je Sun Lim & Jong-Ho Lee & Mi Li & Jichun Shao & Rui Liu, 2022. "Oxygen-sensitive methylation of ULK1 is required for hypoxia-induced autophagy," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28831-6
    DOI: 10.1038/s41467-022-28831-6
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    References listed on IDEAS

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    1. Louise J. Walport & Richard J. Hopkinson & Rasheduzzaman Chowdhury & Rachel Schiller & Wei Ge & Akane Kawamura & Christopher J. Schofield, 2016. "Arginine demethylation is catalysed by a subset of JmjC histone lysine demethylases," Nature Communications, Nature, vol. 7(1), pages 1-12, September.
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