NEK7 accelerates NLRP3 inflammasome activation

Abstract

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 precise activation mechanism remains elusive, impeding inhibitor design. NEK7 was reported as essential for NLRP3 activation, and several newly identified 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 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 should be considered for drug development. We confirmed entrectinib as a NEK7-dependent inhibitor, while other published compounds turned out not to rely on it. 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 fast pathway, while being dispensable for a second, slower mode of NLRP3 activation.