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β-arrestin1 Is Critical for the Full Activation of NLRP3 and NLRC4 Inflammasomes

Kairui Mao, Shuzhen Chen, Yan Wang, Yan Zeng, Yonglei Ma, Yu Hu, Hong Zhang, Shuhui Sun, Xiaodong Wu, Guangxun Meng, Gang Pei and Bing Sun
J Immunol February 15, 2015, 194 (4) 1867-1873; DOI: https://doi.org/10.4049/jimmunol.1401989
Kairui Mao
*State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China;
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Shuzhen Chen
*State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China;
†Department of Microbiology and Immunology, Xiamen Medical College, Xiamen 361008, China;
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Yan Wang
‡Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China;
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Yan Zeng
‡Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China;
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Yonglei Ma
‡Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China;
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Yu Hu
*State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China;
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Hong Zhang
‡Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China;
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Shuhui Sun
§Fudan University School of Medicine, Shanghai 200032, China; and
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Xiaodong Wu
*State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China;
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Guangxun Meng
‡Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China;
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Gang Pei
*State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China;
¶Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, Shanghai 200092, China
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Bing Sun
*State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China;
‡Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China;
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This article has a correction. Please see:

  • Errata - March 01, 2020

Abstract

Inflammasomes are multiprotein complexes that trigger the activation of caspase-1 and the maturation of IL-1β, which are critical for inflammation and control of pathogen infection. Although the function of inflammasomes in immune response and disease development is well studied, the molecular mechanism by which inflammasomes are activated and assembled remains largely unknown. In this study, we found that β-arrestin1, a key regulator of the G protein–coupled receptor signaling pathway, was required for nucleotide-binding domain and leucine-rich repeat containing (NLR) family pyrin domain–containing 3 (NLRP3) and NLR family CARD domain–containing protein 4 (NLRC4) inflammasome–mediated IL-1β production and caspase-1 activation, but it had no effect on absent in melanoma 2 (AIM2) inflammasome activation. Moreover, apoptosis-associated speck-like protein containing a CARD (ASC) pyroptosome, which is ASC aggregation mediating caspase-1 activation, was also impaired in β-arrestin1–deficient macrophages upon NLRP3 or NLRC4, but not AIM2 inflammasome activation. Mechanistic study revealed that β-arrestin1 specifically interacted with NLRP3 and NLRC4 and promoted their self-oligomerization. In vivo, in a monosodium urate crystal (MSU)-induced NLRP3-dependent peritonitis model, MSU-induced IL-1β production and neutrophil flux were significantly reduced in β-arrestin1 knockout mice. Additionally, β-arrestin1 deficiency rescued the weight loss of mice upon log-phase Salmonella typhimurium infection, with less IL-1β production. Taken together, our results indicate that β-arrestin1 plays a critical role in the assembly and activation of two major canonical inflammasomes, and it may provide a new therapeutic target for inflammatory diseases.

Footnotes

  • This work was supported by National 973 Key Project of China Grant 2013CB530504, National 863 Project of China Grants 2012AA02A404 and 2012AA020103, National Natural Science Foundation of China Grants 31030029, 31230024, and 81361120409, National Science and Technology Major Projects of China Grants 2012ZX10002-007-003, 2013ZX10004-101-005, and 2013ZX10004-003-003, and Chinese Academy of Sciences Key Project Grant KJZD-EW-L09-3.

  • The online version of this article contains supplemental material.

  • Abbreviations used in this article:

    AIM2
    absent in melanoma 2
    Arrb1−/−
    β-arrestin1 deficient
    ASC
    apoptosis-associated speck-like protein containing a CARD
    BMDC
    bone marrow–derived dendritic cell
    ω-3 FA
    omega-3 fatty acid
    LDH
    lactate dehydrogenase
    MSU
    monosodium urate
    NLR
    nucleotide-binding domain and leucine-rich repeat containing
    NLRC4
    NLR family CARD domain–containing protein 4
    NLRP3
    NLR family pyrin domain–containing 3
    NMDA
    N-methyl-d-aspartate
    poly(dA:dT)
    poly(deoxyadenylic-thymidylic) acid
    WT
    wild-type.

  • Received August 5, 2014.
  • Accepted December 5, 2014.
  • Copyright © 2015 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 194 (4)
The Journal of Immunology
Vol. 194, Issue 4
15 Feb 2015
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β-arrestin1 Is Critical for the Full Activation of NLRP3 and NLRC4 Inflammasomes
Kairui Mao, Shuzhen Chen, Yan Wang, Yan Zeng, Yonglei Ma, Yu Hu, Hong Zhang, Shuhui Sun, Xiaodong Wu, Guangxun Meng, Gang Pei, Bing Sun
The Journal of Immunology February 15, 2015, 194 (4) 1867-1873; DOI: 10.4049/jimmunol.1401989

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β-arrestin1 Is Critical for the Full Activation of NLRP3 and NLRC4 Inflammasomes
Kairui Mao, Shuzhen Chen, Yan Wang, Yan Zeng, Yonglei Ma, Yu Hu, Hong Zhang, Shuhui Sun, Xiaodong Wu, Guangxun Meng, Gang Pei, Bing Sun
The Journal of Immunology February 15, 2015, 194 (4) 1867-1873; DOI: 10.4049/jimmunol.1401989
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