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论文题目: beta-arrestin1 Is Critical for the Full Activation of NLRP3 and NLRC4 Inflammasomes
英文论文题目: beta-arrestin1 Is Critical for the Full Activation of NLRP3 and NLRC4 Inflammasomes
第一作者: Mao, KR; Chen, SZ; Wang, Y; Zeng, Y; Ma, YL; Hu, Y; Zhang, H; Sun, SH; Wu, XD; Meng, GX; Pei, G; Sun, B
英文第一作者: Mao, KR; Chen, SZ; Wang, Y; Zeng, Y; Ma, YL; Hu, Y; Zhang, H; Sun, SH; Wu, XD; Meng, GX; Pei, G; Sun, B
联系作者: Sun, B (reprint author), Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, State Key Lab Cell Biol, 320 Yueyang Rd, Shanghai 200031, Peoples R China.
英文联系作者: Sun, B (reprint author), Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, State Key Lab Cell Biol, 320 Yueyang Rd, Shanghai 200031, Peoples R China.
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发表年度: 2015
卷: 194
期: 4
页码: 1867-1873
摘要: Inflammasomes are multiprotein complexes that trigger the activation of caspase-1 and the maturation of IL-1 beta, 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 beta-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-1 beta 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 beta-arrestin1-deficient macrophages upon NLRP3 or NLRC4, but not AIM2 inflammasome activation. Mechanistic study revealed that b-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-1 beta production and neutrophil flux were significantly reduced in beta-arrestin1 knockout mice. Additionally, beta-arrestin1 deficiency rescued the weight loss of mice upon log-phase Salmonella typhimurium infection, with less IL-1 beta production. Taken together, our results indicate that beta-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.
英文摘要: Inflammasomes are multiprotein complexes that trigger the activation of caspase-1 and the maturation of IL-1 beta, 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 beta-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-1 beta 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 beta-arrestin1-deficient macrophages upon NLRP3 or NLRC4, but not AIM2 inflammasome activation. Mechanistic study revealed that b-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-1 beta production and neutrophil flux were significantly reduced in beta-arrestin1 knockout mice. Additionally, beta-arrestin1 deficiency rescued the weight loss of mice upon log-phase Salmonella typhimurium infection, with less IL-1 beta production. Taken together, our results indicate that beta-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.
刊物名称: JOURNAL OF IMMUNOLOGY
英文刊物名称: JOURNAL OF IMMUNOLOGY
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学科: Immunology
英文学科: Immunology
影响因子: 4.922
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论文类别: Article
英文论文类别: Article
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