自噬和核糖核蛋白颗粒,如P体(PBs)和应力颗粒,代表维持细胞稳态的重要应激反应。已知SQSTM1/p62相分离液滴在选择性自噬中起关键作用;然而,目前尚不清楚p62是否可以作为除了自噬液滴之外的另一种形式存在。这里,我们发现,在应力条件下,包括蛋白毒性,内毒素,和氧化,自噬p62液滴转化为一种扩大的PBs,称为p62依赖性P-体(pd-PBs)。p62相分离对于pd-PBs的成核至关重要。机械上,pd-PBs是通过p62和DDX6之间的相互作用在压力刺激时增强的p62液滴形成触发的,DDX6是DEAD盒ATPase。功能上,pd-PBs募集NLRP3炎性体衔接子ASC以组装NLRP3炎性体并诱导炎症相关的细胞毒性。我们的研究表明,p62液滴转化为PB作为一种应激反应,激活NLRP3炎性体过程,表明持续pd-PBs导致NLRP3依赖性炎症毒性。
Autophagy and ribonucleoprotein granules, such as P-bodies (PBs) and stress granules, represent vital stress responses to maintain cellular homeostasis. SQSTM1/p62 phase-separated droplets are known to play critical roles in selective autophagy; however, it is unknown whether p62 can exist as another form in addition to its autophagic droplets. Here, we found that, under stress conditions, including proteotoxicity, endotoxicity, and oxidation, autophagic p62 droplets are transformed to a type of enlarged PBs, termed p62-dependent P-bodies (pd-PBs). p62 phase separation is essential for the nucleation of pd-PBs. Mechanistically, pd-PBs are triggered by enhanced p62 droplet formation upon stress stimulation through the interactions between p62 and DDX6, a DEAD-box ATPase. Functionally, pd-PBs recruit the NLRP3 inflammasome adaptor ASC to assemble the NLRP3 inflammasome and induce inflammation-associated cytotoxicity. Our study shows that p62 droplet-to-PB transformation acts as a stress response to activate the NLRP3 inflammasome process, suggesting that persistent pd-PBs lead to NLRP3-dependent inflammation toxicity.