NEK7 Accelerates NLRP3 Inflammasome Activation.

The NLRP3 inflammasome is a major driver of immunopathology, making it a sought-after drug target. In spite of two decades of intense research, its activation mechanism is still poorly understood, impeding inhibitor design. NEK7 was reported to be essential for NLRP3 activation, and several newly identified NLRP3 inhibitors were suggested to act by interfering with their interaction. Here we report that NEK7 accelerates, but is in principle dispensable for NLRP3 activation. The onset of inflammasome activation on the single-cell level was unaltered in the absence of NEK7, yet the rate of cells to undergo inflammasome formation and subsequent pyroptosis was approximately 4-fold reduced. Therefore, therapeutic targeting of the NEK7-NLRP3 interaction might have an incomplete effect, which has to be considered for drug development. We confirmed entrectinib as a NEK7-dependent inhibitor, while other published drug candidates turned out not to rely on its presence. Our results support two possible scenarios for the role of NEK7 in NLRP3 activation: either, NEK7 accelerates one unique pathway of NLRP3 activation, or it is essential for a first, fast pathway, while being dispensable for a second, slower NLRP3 activation pathway.