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

Author

Listed:
  • Jing Jin

    (Institute of Immunology, Zhejiang University School of Medicine
    National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University)

  • 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
    National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University
    Chinese Academy of Medical Sciences)

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.

Suggested Citation

  • Jing Jin & Qian Yu & Chaofeng Han & Xiang Hu & Sheng Xu & Qingqing Wang & Jianli Wang & Nan Li & Xuetao Cao, 2013. "LRRFIP2 negatively regulates NLRP3 inflammasome activation in macrophages by promoting Flightless-I-mediated caspase-1 inhibition," Nature Communications, Nature, vol. 4(1), pages 1-8, October.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms3075
    DOI: 10.1038/ncomms3075
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