Department of Physiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
Department of Physiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
Cell Rep. 2023 Feb 28;42(2):112037. doi: 10.1016/j.celrep.2023.112037. Epub 2023 Jan 25.
In response to lysosomal damage, cells engage several quality-control mechanisms, including the selective isolation and degradation of damaged lysosomes by lysophagy. Here, we report that the selective autophagy adaptor SQSTM1/p62 is recruited to damaged lysosomes in both HeLa cells and neurons and is required for lysophagic flux. The Phox and Bem1p (PB1) domain of p62 mediates oligomerization and is specifically required for lysophagy. Consistent with this observation, we find that p62 forms condensates on damaged lysosomes. These condensates are precisely tuned by the small heat shock protein HSP27, which is phosphorylated in response to lysosomal injury and maintains the liquidity of p62 condensates, facilitating autophagosome formation. Mutations in p62 have been identified in patients with amyotrophic lateral sclerosis (ALS); ALS-associated mutations in p62 impair lysophagy, suggesting that deficits in this pathway may contribute to neurodegeneration. Thus, p62 condensates regulated by HSP27 promote lysophagy by forming platforms for autophagosome biogenesis at damaged lysosomes.
针对溶酶体损伤，细胞会启动几种质量控制机制，包括通过自噬作用选择性地隔离和降解受损的溶酶体。在这里，我们报告说，选择性自噬衔接蛋白 SQSTM1/p62 可募集到 HeLa 细胞和神经元中的受损溶酶体，并且是溶酶体自噬流所必需的。p62 的 Phox 和 Bem1p（PB1）结构域介导寡聚化，并且特异性地需要用于溶酶体自噬。与这一观察结果一致，我们发现 p62 在受损的溶酶体上形成了凝聚物。这些凝聚物被小热休克蛋白 HSP27 精确地调节，HSP27 会响应溶酶体损伤而被磷酸化，并保持 p62 凝聚物的流动性，从而促进自噬体的形成。在肌萎缩侧索硬化症（ALS）患者中已鉴定出 p62 的突变；p62 的 ALS 相关突变会损害溶酶体自噬，这表明该途径的缺陷可能导致神经退行性变。因此，由 HSP27 调节的 p62 凝聚物通过在受损的溶酶体上形成自噬体生物发生的平台来促进溶酶体自噬。
