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

Abstract

Lysosomes are membrane-bound organelles that regulate cellular proteostasis. Loss of lysosomal integrity initiates cell death pathways. Thus, cells must rely on quality control mechanisms for protection, including the selective isolation and degradation of damaged lysosomes by lysophagy. Here, we report that the selective autophagy receptor SQSTM1/p62 is an essential lysophagy receptor recruited to damaged lysosomes in both HeLa cells and neurons. p62 oligomers form liquid-like condensates that are critical in lysophagy. These condensates are regulated by the small heat shock protein HSP27, which binds p62 to prevent p62 aggregation and facilitate autophagosome formation. Mutations in p62 are implicated in Amyotrophic Lateral Sclerosis (ALS), and expression of ALS-associated mutations in p62 impair lysophagy, suggesting that deficits in this pathway may contribute to the cellular pathogenesis of ALS. Thus, p62 oligomers cooperate with HSP27 to promote lysophagy by forming a platform for autophagosome biogenesis at damaged lysosomes.