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Requirement for p62 acetylation in the aggregation of ubiquitylated proteins under nutrient stress

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  • Zhiyuan You

    (Zhejiang University School of Medicine)

  • Wen-Xue Jiang

    (National Center for Magnetic Resonance at Wuhan, Wuhan Institute of Physics and Mathematics of the Chinese Academy of Sciences)

  • Ling-Yun Qin

    (National Center for Magnetic Resonance at Wuhan, Wuhan Institute of Physics and Mathematics of the Chinese Academy of Sciences)

  • Zhou Gong

    (National Center for Magnetic Resonance at Wuhan, Wuhan Institute of Physics and Mathematics of the Chinese Academy of Sciences)

  • Wei Wan

    (Zhejiang University School of Medicine)

  • Jin Li

    (Zhejiang University School of Medicine)

  • Yusha Wang

    (Zhejiang University School of Medicine)

  • Hongtao Zhang

    (Zhejiang University School of Medicine)

  • Chao Peng

    (Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences)

  • Tianhua Zhou

    (Zhejiang University School of Medicine)

  • Chun Tang

    (National Center for Magnetic Resonance at Wuhan, Wuhan Institute of Physics and Mathematics of the Chinese Academy of Sciences)

  • Wei Liu

    (Zhejiang University School of Medicine
    Joint Institute of Genetics and Genomics Medicine between Zhejiang University and University of Toronto)

Abstract

Autophagy receptor p62/SQSTM1 promotes the assembly and removal of ubiquitylated proteins by forming p62 bodies and mediating their encapsulation in autophagosomes. Here we show that under nutrient-deficient conditions, cellular p62 specifically undergoes acetylation, which is required for the formation and subsequent autophagic clearance of p62 bodies. We identify K420 and K435 in the UBA domain as the main acetylation sites, and TIP60 and HDAC6 as the acetyltransferase and deacetylase. Mechanically, acetylation at both K420 and K435 sites enhances p62 binding to ubiquitin by disrupting UBA dimerization, while K435 acetylation also directly increases the UBA-ubiquitin affinity. Furthermore, we show that acetylation of p62 facilitates polyubiquitin chain-induced p62 phase separation. Our results suggest an essential role of p62 acetylation in the selective degradation of ubiquitylated proteins in cells under nutrient stress, by specifically regulating the assembly of p62 bodies.

Suggested Citation

  • Zhiyuan You & Wen-Xue Jiang & Ling-Yun Qin & Zhou Gong & Wei Wan & Jin Li & Yusha Wang & Hongtao Zhang & Chao Peng & Tianhua Zhou & Chun Tang & Wei Liu, 2019. "Requirement for p62 acetylation in the aggregation of ubiquitylated proteins under nutrient stress," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-13718-w
    DOI: 10.1038/s41467-019-13718-w
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    Cited by:

    1. Beibei Fu & Yan Xiong & Zhou Sha & Weiwei Xue & Binbin Xu & Shun Tan & Dong Guo & Feng Lin & Lulu Wang & Jianjian Ji & Yang Luo & Xiaoyuan Lin & Haibo Wu, 2023. "SEPTIN2 suppresses an IFN-γ-independent, proinflammatory macrophage activation pathway," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    2. Xuezhao Feng & Daxiao Sun & Yanchang Li & Jinpei Zhang & Shiyu Liu & Dachuan Zhang & Jingxiang Zheng & Qing Xi & Haisha Liang & Wenkang Zhao & Ying Li & Mengbo Xu & Jiayu He & Tong Liu & Ayshamgul Has, 2023. "Local membrane source gathering by p62 body drives autophagosome formation," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    3. Yunpeng Huang & Zhihui Wan & Yinglu Tang & Junxuan Xu & Bretton Laboret & Sree Nallamothu & Chenyu Yang & Boxiang Liu & Rongze Olivia Lu & Bingwei Lu & Juan Feng & Jing Cao & Susan Hayflick & Zhihao W, 2022. "Pantothenate kinase 2 interacts with PINK1 to regulate mitochondrial quality control via acetyl-CoA metabolism," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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