Cytoplasmic DAXX drives SQSTM1/p62 phase condensation to activate Nrf2-mediated stress response

Yi Yang, Thea L. Willis, Robert W. Button, Conor J. Strang, Yuhua Fu, Xue Wen, Portia R. C. Grayson, Tracey Evans, Rebecca J. Sipthorpe, Sheridan L. Roberts, Bing Hu, Jianke Zhang, Boxun Lu and Shouqing Luo ()
Additional contact information
Yi Yang: University of Plymouth
Thea L. Willis: University of Plymouth
Robert W. Button: University of Plymouth
Conor J. Strang: University of Plymouth
Yuhua Fu: Fudan University
Xue Wen: Fudan University
Portia R. C. Grayson: University of Plymouth
Tracey Evans: University of Plymouth
Rebecca J. Sipthorpe: University of Plymouth
Sheridan L. Roberts: University of Plymouth
Bing Hu: University of Plymouth
Jianke Zhang: Thomas Jefferson University
Boxun Lu: Fudan University
Shouqing Luo: University of Plymouth

Nature Communications, 2019, vol. 10, issue 1, 1-18

Abstract: Abstract Autophagy cargo recognition and clearance are essential for intracellular protein quality control. SQSTM1/p62 sequesters intracellular aberrant proteins and mediates cargo delivery for their selective autophagic degradation. The formation of p62 non-membrane-bound liquid compartments is critical for its function as a cargo receptor. The regulation of p62 phase separation/condensation has yet been poorly characterised. Using an unbiased yeast two-hybrid screening and complementary approaches, we found that DAXX physically interacts with p62. Cytoplasmic DAXX promotes p62 puncta formation. We further elucidate that DAXX drives p62 liquid phase condensation by inducing p62 oligomerisation. This effect promotes p62 recruitment of Keap1 and subsequent Nrf2-mediated stress response. The present study suggests a mechanism of p62 phase condensation by a protein interaction, and indicates that DAXX regulates redox homoeostasis, providing a mechanistic insight into the prosurvival function of DAXX.

Date: 2019
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DOI: 10.1038/s41467-019-11671-2

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