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

  • Nat Commun. 2019 Dec 19;10(1):5792. doi: 10.1038/s41467-019-13718-w.
Zhiyuan You  1 ,  Wen-Xue Jiang  2 ,  Ling-Yun Qin  2 ,  Zhou Gong  2 ,  Wei Wan  1 ,  Jin Li  1 ,  Yusha Wang  1 ,  Hongtao Zhang  1 ,  Chao Peng  3 ,  Tianhua Zhou  1 ,  Chun Tang  4 ,  Wei Liu  5  6
Affiliations
  • 1. Department of Biochemistry and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.
  • 2. CAS Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic Molecular Physics, National Center for Magnetic Resonance at Wuhan, Wuhan Institute of Physics and Mathematics of the Chinese Academy of Sciences, Wuhan, 430071, China.
  • 3. National Center for Protein Science Shanghai, Institute of Biochemistry and Cell Biology, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.
  • 4. CAS Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic Molecular Physics, National Center for Magnetic Resonance at Wuhan, Wuhan Institute of Physics and Mathematics of the Chinese Academy of Sciences, Wuhan, 430071, China. [email protected].
  • 5. Department of Biochemistry and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China. [email protected].
  • 6. Joint Institute of Genetics and Genomics Medicine between Zhejiang University and University of Toronto, Hangzhou, 310058, China. [email protected].
PMID: 31857589 DOI: 10.1038/s41467-019-13718-w
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.