Molecular basis for NEK7-mediated NLRP3 inflammasome activation

Abstract

Abstract The NLRP3 inflammasome is a critical component of the innate immune system that is activated by microbial infections and cellular stress signals. The molecular mechanism of NLRP3 inflammasome activation remains not fully understood. As an NLRP3-interacting partner, NEK7 has emerged as a critical mediator for NLRP3 inflammasome activation. In contrast to NEK7, NEK6, the closely related member of the NEK family, does not support NLRP3 inflammasome activation. Here, we show that the NEK7 catalytic domain, which shares a high sequence identity with the counterpart of NEK6, mediates its interaction with NLRP3 and inflammasome activation. Within their catalytic domains, a single amino acid residue at a corresponding position (R121NEK7, Q132NEK6) differentiates their function in NLRP3 inflammasome activation. Surprisingly, the substitution of the glutamine residue to arginine residue at position 132 confers NEK6 the ability of NLRP3 binding and inflammasome activation. In addition, NEK7 is reported to interact with the LRR domain of NLRP3. We show that the LRR domain self-associates independently of NEK7 and promotes inflammasome assembly and activation in macrophages at the physiological condition. Supported by NIH R01AI148544