Tyrosine Phosphorylation of NLRP3 by Src Family Protein Tyrosine Kinase Lyn Suppresses NLRP3 Inflammasome Activation

Abstract The NLRP3 inflammasome is a multi-protein complex that triggers the activation of inflammatory caspase-1 and the maturation of IL-1β in response to microbes and danger signals in host cells. However, how the NLRP3 inflammasome is regulated is not fully understood. Here, we show that NLRP3 is tyrosine phosphorylated upon activation of the NLRP3 inflammasome, and that NLRP3 tyrosine phosphorylation correlates with its ubiquitination. Further, we identified Lyn as the protein tyrosine kinase that phosphorylates NLRP3 at Tyr 918, which facilitates its ubiquitination and proteasome-mediated degradation. Consistent with these data, NLRP3 tyrosine phosphorylation and ubiquitination is abrogated in macrophages lacking Lyn, which correlates with heightened IL-1 production. Therefore, our data demonstrate that Lyn-mediated tyrosine phosphorylation of NLRP3 is a prerequisite for its ubiquitination, thus dampening NLRP3 inflammasome activity.