Institute of Immunology, Zhejiang University School of Medicine, 866 Yu-Hang-Tang Road, Hangzhou 310058, China.
Nat Commun. 2013;4:2075. doi: 10.1038/ncomms3075.
The NLRP3 inflammasome is the most characterized inflammasome activated by cellular infection or stress, which is responsible for the maturation of proinflammatory cytokines IL-1β and IL-18. The precise molecular mechanism for negative regulation of NLRP3 inflammasome activation needs to be further defined. Here we identify leucine-rich repeat Fli-I-interacting protein 2 (LRRFIP2) as an NLRP3-associated protein and an inhibitor for NLRP3 inflammasome activation. LRRFIP2 binds to NLRP3 via its N terminus upon NLRP3 inflammasome activation, and also interacts with Flightless-I, a pseudosubstrate of caspase-1, via its Coil motif. Knockdown of Flightless-I significantly promotes NLRP3 inflammasome activation. LRRFIP2 enhances the interaction between Flightless-I and caspase-1, facilitating the inhibitory effect of Flightless-I on caspase-1 activation. Furthermore, silencing of Flightless-I abrogates the inhibitory effect of LRRFIP2 on NLRP3 inflammasome. These data demonstrate that LRRFIP2 inhibits NLRP3 inflammasome activation by recruiting the caspase-1 inhibitor Flightless-I, thus outlining a new mechanism for negative regulation of NLRP3 inflammasome.
NLRP3 炎性小体是最具特征的细胞感染或应激激活的炎性小体，负责促炎细胞因子 IL-1β 和 IL-18 的成熟。 NLRP3 炎性小体激活的负调控的精确分子机制需要进一步定义。在这里，我们确定富含亮氨酸重复 Fli-I 相互作用蛋白 2（LRRFIP2）是 NLRP3 相关蛋白和 NLRP3 炎性小体激活的抑制剂。LRRFIP2 在 NLRP3 炎性小体激活时通过其 N 端与 NLRP3 结合，并且还通过其卷曲结构域与 Flightless-I（半胱天冬酶-1 的假底物）相互作用。Flightless-I 的敲低显著促进 NLRP3 炎性小体的激活。LRRFIP2 增强了 Flightless-I 和半胱天冬酶-1 之间的相互作用，促进了 Flightless-I 对半胱天冬酶-1 激活的抑制作用。此外，沉默 Flightless-I 可消除 LRRFIP2 对 NLRP3 炎性小体的抑制作用。这些数据表明，LRRFIP2 通过募集半胱天冬酶-1 抑制剂 Flightless-I 来抑制 NLRP3 炎性小体的激活，从而为 NLRP3 炎性小体的负调控提供了一个新的机制。
Zotero 插件