SQSTM1/p62-LC3A–mediated autophagic clearance of stress granules prevents apoptosis under hyperosmotic stress

Stress granules (SGs) are transient, membraneless assemblies that form in response to cellular stress and typically disassemble when stress resolves. Their persistence has been linked to neurodegenerative disease. Here we show that LC3A has a selective role in the autophagic clearance of SGs formed during hyperosmotic stress. LC3A, but not LC3B or LC3C, associates with SGs, and depletion of LC3A impairs their removal. LC3A also promotes clearance of pathogenic inclusions containing TDP-43 or poly(GR) dipeptides from C9orf72 expansions. Proteomic analysis reveals enrichment of the autophagy receptor SQSTM1/p62 in SGs, supporting its role in SG degradation. SGs are also enriched in mitochondrial and apoptosis-related proteins, consistent with an anti-apoptotic function potentially linked to mitochondrial proximity. However, prolonged stress activates CASP3 and promotes apoptosis, which is exacerbated by defective SG clearance. These findings highlight the critical role of the SQSTM1–LC3A axis in SG turnover and cell survival under chronic stress.