A dominant-negative regulatory mechanism of SQSTM1 droplets-based autophagy.

SQSTM1/p62 is an autophagy receptor, forming droplets to sequester intracellular polyubiquitinated cargo and mediate its delivery for autophagic clearance. SQSTM1 droplets can function as platforms to allow the formation of autophagosomes at their surfaces. It would be interesting to understand how SQSTM1-droplet formation is regulated. We have shown that inflammatory toxicity induces SQSTM1 cleavage by CASP6 at a novel cleavage site, D256. The C-terminal cleavage product is unlikely to be functional, because it is hardly detectable, possibly due to its rapid turnover. The SQSTM1 N-terminal cleavage product (SQSTM1-N) exerts a dominant-negative effect on SQSTM1-droplet production, in turn attenuating SQSTM1 droplets-based autophagosome formation. Our study suggests that the CASP6-SQSTM1 axis negatively regulates SQSTM1 droplets-based autophagy under certain stress conditions.