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NLRP3 activation and mitosis are mutually exclusive events coordinated by NEK7, a new inflammasome component

Shi, H;Wang, Y;Li, X;Zhan, X;Tang, M;Fina, M;Su, L;Pratt, D;Bu, CH;Hildebrand, S;Lyon, S;Scott, L;Quan, J;Sun, Q;Russell, J;Arnett, S;Jurek, P;Chen, D;Kravchenko, VV;Mathison, JC;Moresco, EM;Monson, NL;Ulevitch, RJ;Beutler, B;

The NLRP3 inflammasome responds to microbes and danger signals by processing and activating proinflammatory cytokines, including interleukin 1 (IL-1) and IL-18. We found here that activation of the NLRP3 inflammasome was restricted to interphase of the cell cycle by NEK7, a serine-threonine kinase previously linked to mitosis. Activation of the NLRP3 inflammasome required NEK7, which bound to the leucine-rich repeat domain of NLRP3 in a kinase-independent manner downstream of the induction of mitochondrial reactive oxygen species (ROS). This interaction was necessary for the formation of a complex containing NLRP3 and the adaptor ASC, oligomerization of ASC and activation of caspase-1. NEK7 promoted the NLRP3-dependent cellular inflammatory response to intraperitoneal challenge with monosodium urate and the development of experimental autoimmune encephalitis in mice. Our findings suggest that NEK7 serves as a cellular switch that enforces mutual exclusivity of the inflammasome response and cell division.