上海科技大学知识管理系统

Stress granules (SGs) are membraneless organelles formed in response to cellular stress, and they play a key role in protecting cells by sequestering and regulating stress-related molecules. Disruptions in SG dynamics have been linked to neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In our previous study, we demonstrated high-resolution, timeresolved proteomic profiling to track the compositional and functional transitions throughout the SG life cycle and provided insights into how SGs achieve their diverse, stress-type-specific functions (Hu et al., Nature Communications, 2023). Furthermore, we investigated protein quality control mechanisms regulating SG homeostasis under various stress conditions (Yang et al., Autophagy, 2023). In this study, we delved into the detailed mechanisms governing the autophagic degradation of high salt-induced SGs and SG-colocalized pathological inclusions. We established a high salt-induced SG model and identified LC3 isoform A (LC3A) as the key protein mediating the autophagic degradation of these SGs. Through proteomic analysis of affinity-purified SGs under prolonged high salt conditions, coupled with comprehensive immunostaining and genetic analysis, we discovered that LC3A specifically colocalizes with SGs and facilitates their degradation. The SG proteome also revealed various key autophagyrelated proteins, including the autophagy receptor SQSTM1/p62 and the segregase VCP, whose depletion markedly compromised SG degradation. Additionally, LC3A-mediated degradation was critical for clearing pathogenic inclusions formed by disease-associated variants. These findings highlight the pivotal role of the SQSTM1-LC3A axis in the autophagic degradation of SGs under chronic stress and pathological conditions, providing new insights into the cellular stress response and its implications for diseases.