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

Yi Yang,Thea L Willis,Yuhua Fu,Jianke Zhang,Portia R C Grayson,Tracey Evans,Conor J Strang,Shouqing Luo,Boxun Lu,Robert W Button,Xue Wen,Rebecca J Sipthorpe,Bing Hu,Sheridan L Roberts

doi:10.1038/s41467-019-11671-2

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.

Highlights

Autophagy cargo recognition and clearance are essential for intracellular protein quality control
The present study provides a mechanistic insight into p62 phase condensation, and the prosurvival function of DAXX
DAXX is a p62 interaction protein. p62 body formation is required for its simultaneous interactions with ubiquitinated protein cargos and LC339

Summary

Introduction

Autophagy cargo recognition and clearance are essential for intracellular protein quality control. We further elucidate that DAXX drives p62 liquid phase condensation by inducing p62 oligomerisation. This effect promotes p62 recruitment of Keap[1] and subsequent Nrf2-mediated stress response. Metazoan cargo receptors, including p62/SQSTM1, NBR1, Optineurin and NDP52, recognise the cargo via their ubiquitin binding[1,2,9,20] Among these receptors, p62 is best characterised to mediate autophagic clearance of polyubiquitinated cargos such as aggregated proteins. The DAXX-driven p62 phase condensation promotes p62 recruitment of Keap[1] and subsequent Nrf2-mediated stress response. The present study provides a mechanistic insight into p62 phase condensation, and the prosurvival function of DAXX

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