LRRFIP2 negatively regulates NLRP3 inflammasome activation in macrophages by promoting Flightless-I-mediated caspase-1 inhibition

Jing Jin, Qian Yu, Chaofeng Han, Xiang Hu, Sheng Xu, Qingqing Wang, Jianli Wang, Nan Li and Xuetao Cao ()
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Jing Jin: Institute of Immunology, Zhejiang University School of Medicine
Qian Yu: National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University
Chaofeng Han: National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University
Xiang Hu: Chinese Academy of Medical Sciences
Sheng Xu: National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University
Qingqing Wang: Institute of Immunology, Zhejiang University School of Medicine
Jianli Wang: Institute of Immunology, Zhejiang University School of Medicine
Nan Li: National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University
Xuetao Cao: Institute of Immunology, Zhejiang University School of Medicine

Nature Communications, 2013, vol. 4, issue 1, 1-8

Abstract: Abstract 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.

Date: 2013
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DOI: 10.1038/ncomms3075

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