Enhanced liquidity of p62 droplets mediated by Smurf1 links Nrf2 activation and autophagy

Cell & Bioscience

Research

Qin Xia¹  Lei Dong¹  Chengwei Wu¹  Wanting Xu¹  Hanfei Zheng¹  Liqun Liu¹  Yang Li¹ 

[1] School of Life Science, Beijing Institute of Technology, No. 5, South Street, Zhongguancun, Haidian District, Beijing, China;

关键词: Smurf1;    Protein homeostasis;    p62-liquid droplets;   

DOI  :  10.1186/s13578-023-00978-9

 received in 2022-08-13, accepted in 2023-02-02,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundMacro-autophagy/Autophagy is an evolutionarily well-conserved recycling process to maintain the balance through precise spatiotemporal regulation. However, the regulatory mechanisms of biomolecular condensates by the key adaptor protein p62 via liquid-liquid phase separation (LLPS) remain obscure.ResultsIn this study, we showed that E3 ligase Smurf1 enhanced Nrf2 activation and promoted autophagy by increasing p62 phase separation capability. Specifically, the Smurf1/p62 interaction improved the formation and material exchange of liquid droplets compared with p62 single puncta. Additionally, Smurf1 promoted the competitive binding of p62 with Keap1 to increase Nrf2 nuclear translocation in p62 Ser349 phosphorylation-dependent manner. Mechanistically, overexpressed Smurf1 increased the activation of mTORC1 (mechanistic target of rapamycin complex 1), in turn leading to p62 Ser349 phosphorylation. Nrf2 activation increased the mRNA levels of Smurf1, p62, and NBR1, further promoting the droplet liquidity to enhance oxidative stress response. Importantly, we showed that Smurf1 maintained cellular homeostasis by promoting cargo degradation through the p62/LC3 autophagic pathway.ConclusionsThese findings revealed the complex interconnected role among Smurf1, p62/Nrf2/NBR1, and p62/LC3 axis in determining Nrf2 activation and subsequent clearance of condensates through LLPS mechanism.

【 授权许可】

CC BY   
© The Author(s) 2023

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