SQSTM1/P62 promotes lysophagy via formation of liquid-like condensates maintained by HSP27

ABSTRACT

Injury to the lysosome engages a series of quality control mechanisms that mitigate cellular stress. One such mechanism is the degradation of these organelles by lysophagy, the selective autophagy of damaged lysosomes. In recent work, we have shown a requirement for the selective autophagy receptor SQSTM1/p62 in lysophagy. SQSTM1 is robustly recruited to damaged lysosomes in both HeLa cells and neurons, promoting lysophagy through the formation of liquid-phase separated condensates. The formation of SQSTM1 condensates occurs via PB1 domain oligomerization; importantly, we demonstrate that the small heat shock protein HSP27 is required to maintain the liquidity of SQSTM1 condensates. HSP27 is dynamically regulated following lysosomal damage, with phosphorylation at multiple residues required to respond to lysosomal permeabilization. As mutations in SQSTM1 associated with amyotrophic lateral sclerosis (ALS) cause deficits in lysophagy, our work suggests a causal link between the pathogenesis of ALS and deficits in lysophagy. In sum, we observe that SQSTM1 facilitates lysophagy via the formation of HSP27-regulated phase condensates, which we propose serve as a platform for autophagosome biogenesis at damaged lysosomes.

Abbreviations

SQSTM1/p62: Sequestosome-1; HSP27: Heat shock protein 27; LLPS: liquid-liquid phase separation; iPSC: induced pluripotent stem cell; PB1: Phox and Bem1p; FRAP: fluorescence recovery after photo-bleaching; ATG: autophagy-related; ALS: amyotrophic lateral sclerosis

KEYWORDS:

• Lysosomes
• lysophagy
• Sqstm1/P62
• HSP27
• phase separation
• neurodegeneration

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The work was supported by the National Institutes of Health [F31 NS125954]; National Institute of Neurological Disorders and Stroke - U.S. (Maryland) [R01 NS060698]