Sestrin2 acts as a negative regulator of inflammasome activation by inducing mitophagy

Abstract

In “danger” conditions, such as infections, the NLRP3 inflammasome complex is positively regulated by mitochondria-generated reactive oxygen species and negatively regulated by autophagy. Thus, tight regulation of both mitochondrial integrity and autophagy is essential for proper inflammasome activation. Here, I demonstrate that Sestrin2 suppressed continuous inflammasome activation by preserving mitochondrial homeostasis through inducing selective autophagy. Sestrin2 plays a dual role to remove damaged mitochondria caused by stimulation with LPS and ATP in macrophages. First, Sestrin2 facilitates the perinuclear clustering of damaged mitochondria by mediating aggregation of p62/SQSTM1 and its recruitment to Lys 63 ubiquitins on mitochondria surface. Second, Sestrin2 induces autophagosome formation and mitophagy through maintenance of ULK1 stability. Thus, both Sestrin2- and p62-deficient mice had more damaged mitochondria, and produced more caspase-1-dependent cytokines, including IL-1β and IL-18, and had higher mortality in sepsis models. These findings identify a novel role of Sestrin2 and p62 for protection against incessant inflammation.