Preprint Highlight: The selective autophagy receptor p62 and the heat shock protein HSP27 facilitate lysophagy via the formation of phase-separated condensates.

Abstract

Ruptured lysosomes are cleared by lysophagy, a selective form of macroautophagy. Thus lysophagy protects cells against lysosomal cell death, a form of cell death caused by the release of lysosomal proteases to the cytosol from ruptured lysosomes. However, the mechanism underlying this process is still incomplete. Using HeLa cells, rat primary neurons, and human neurons, the authors show that SQSTM1/p62 is a key lysophagy adaptor that forms phase-separated condensates. Mechanistically, p62 oligomerizes but remains in liquid phase to ensure the formation of an autophagosome along the ruptured lysosome. The liquidlike state of p62 is maintained by the small chaperone HSP27. Amyotrophic lateral sclerosis (ALS)-associated mutations in p62 prevent its localization and disrupt lysophagy. These results demonstrate a new role of p62 in lysophagy and implicate lysophagy in the pathobiology of ALS.