Histone H3F3/H3.3 chaperone DAXX converts to modulate SQSTM1 phase condensation for NFE2L2 activation.

Macroautophagy/autophagy cargo receptor SQSTM1/p62 puncta or clustering formation is critical for its function in cargo recognition and LC3 interaction. Evidence suggests that SQSTM1 puncta formation is a process of liquid-liquid phase separation. It is poorly understood how SQSTM1 liquid-liquid phase separation is regulated. We found that cytoplasmic DAXX enhances SQSTM1 puncta formation, and further demonstrated that DAXX drives SQSTM1 liquid phase condensation through increasing SQSTM1 oligomerization. DAXX promotes SQSTM1 recruitment of KEAP1, subsequently activating an NFE2L2/NRF2-mediated stress response. This study suggests a new mechanism of SQSTM1 phase condensation by a protein-protein interaction, and indicates that cytoplasmic DAXX can play a role to regulate redox homeostasis.