Department of Biochemistry, Microbiology, and Immunology, Wayne State University, Detroit, MI.
Department of Biochemistry, Microbiology, and Immunology, Wayne State University, Detroit, MI
J Immunol. 2022 Apr 15;208(8):2029-2036. doi: 10.4049/jimmunol.2101154. Epub 2022 Mar 30.
The NOD-like receptor family pyrin domain-containing 3 (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. In this study, we show that the mouse NEK7 catalytic domain, which shares high sequence identity with the counterpart of NEK6, mediates its interaction with NLRP3 and inflammasome activation in mouse macrophages. Within their catalytic domains, a single amino acid residue at a corresponding position (R121, Q132) differentiates their function in NLRP3 inflammasome activation. Surprisingly, substitution of the glutamine residue to an arginine residue at position 132 confers NEK6 the ability of NLRP3 binding and inflammasome activation in mouse macrophages. Furthermore, our results suggest a structural pocket surrounding the residue R121 of NEK7 that is essential for NLRP3 binding and inflammasome activation.
NOD 样受体家族包含 pyrin 结构域的 3（NLRP3）炎性小体是先天免疫系统的关键组成部分，可被微生物感染和细胞应激信号激活。NLRP3 炎性小体激活的分子机制尚不完全清楚。作为 NLRP3 的相互作用伙伴，NEK7 已成为 NLRP3 炎性小体激活的关键介质。与 NEK7 不同，NEK 家族的密切相关成员 NEK6 不支持 NLRP3 炎性小体的激活。在这项研究中，我们表明，与 NEK6 相对应的具有高度序列同一性的小鼠 NEK7 催化结构域介导其与 NLRP3 的相互作用，并在小鼠巨噬细胞中激活炎性小体。在它们的催化结构域中，相应位置（R121，Q132）上的单个氨基酸残基区分了它们在 NLRP3 炎性小体激活中的功能。令人惊讶的是，将第 132 位的谷氨酰胺残基替换为精氨酸残基，可使 NEK6 具有与 NLRP3 结合并在小鼠巨噬细胞中激活炎性小体的能力。此外，我们的结果表明，NEK7 的残基 R121 周围存在一个结构口袋，该口袋对于 NLRP3 的结合和炎性小体的激活至关重要。
