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Of NLRP3 and NLRC4 Inflammasomes 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, This information is current as Guangxun Meng, Gang Pei and Bing Sun of October 1, 2021. J Immunol 2015; 194:1867-1873; Prepublished online 12 January 2015; doi: 10.4049/jimmunol.1401989 http://www.jimmunol.org/content/194/4/1867 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2015/01/09/jimmunol.140198 Material 9.DCSupplemental References This article cites 38 articles, 9 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/194/4/1867.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on October 1, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts Errata An erratum has been published regarding this article. Please see next page or: /content/204/5/1410.full.pdf The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2015 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology b-arrestin1 Is Critical for the Full Activation of NLRP3 and NLRC4 Inflammasomes Kairui Mao,*,1 Shuzhen Chen,*,†,1 Yan Wang,‡,1 Yan Zeng,‡ Yonglei Ma,‡ Yu Hu,* Hong Zhang,‡ Shuhui Sun,x Xiaodong Wu,* Guangxun Meng,‡ Gang Pei,*,{ and Bing Sun*,‡ Inflammasomes are multiprotein complexes that trigger the activation of caspase-1 and the maturation of IL-1b, 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 b-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) b and NLR family CARD domain–containing protein 4 (NLRC4) inflammasome–mediated IL-1 production and caspase-1 acti- Downloaded from vation, 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 b-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 monoso- dium urate crystal (MSU)-induced NLRP3-dependent peritonitis model, MSU-induced IL-1b production and neutrophil flux were significantly reduced in b-arrestin1 knockout mice. Additionally, b-arrestin1 deficiency rescued the weight loss of mice upon log- http://www.jimmunol.org/ phase Salmonella typhimurium infection, with less IL-1b production. Taken together, our results indicate that b-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. The Journal of Immunology, 2015, 194: 1867–1873. attern recognition receptors recognize a diverse range of cleotide-binding domain and leucine-rich repeat containing (NLR) microbial components and environmental irritants to in- family proteins or absent in melanoma 2–like (AIM2) receptors (ALR) P duce innate immune responses. Among those, some nu- form multiprotein complexes called inflammasomes with the adaptor apoptosis-associated speck-like protein containing a CARD (ASC) and caspase-1 (1). Once activated, inflammasomes serve as a platform by guest on October 1, 2021 *State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, for caspase-1 activation and IL-1b maturation as well as pyroptosis Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai (2). Canonical inflammasomes, including NLR family pyrin domain– 200031, China; †Department of Microbiology and Immunology, Xiamen Medical College, Xiamen 361008, China; ‡Key Laboratory of Molecular Virology and Im- containing 3 (NLRP3), NLR family CARD domain–containing pro- munology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, tein 4 (NLRC4), and AIM2, once activated by microbial stimuli and Chinese Academy of Sciences, Shanghai 200031, China; xFudan University School of Medicine, Shanghai 200032, China; and {Shanghai Key Laboratory of Signaling endogenous danger signals undergo self-oligomerization to recruit and Disease Research, School of Life Science and Technology, Tongji University, the adaptor protein ASC. This step leads to self-oligomerization of Shanghai 200092, China ASC into a very large supramolecular structure called the ASC 1K.M., S.C., and Y.W. contributed equally to this work. pyroptosome, which recruits and activates procaspase-1, leading to Received for publication August 5, 2014. Accepted for publication December 5, the processing of pro–IL-1b and pro–IL-18 into the active proin- 2014. flammatory cytokines IL-1b and IL-18, respectively (3–5). Although This work was supported by National 973 Key Project of China Grant it has been well established that activation of inflammasomes plays 2013CB530504, National 863 Project of China Grants 2012AA02A404 and 2012AA020103, National Natural Science Foundation of China Grants 31030029, critical roles in microbial- or danger-associated signal–induced inflam- 31230024, and 81361120409, National Science and Technology Major Projects of matory responses, how inflammatory stimuli promote the forma- China Grants 2012ZX10002-007-003, 2013ZX10004-101-005, and 2013ZX10004- 003-003, and Chinese Academy of Sciences Key Project Grant KJZD-EW-L09-3. tion and activation of the inflammasomes remains largely unclear. b-arrestins are multifunctional proteins that play critical roles in Address correspondence and reprint requests to Dr. Bing Sun and Dr. Gang Pei, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, the G protein–coupled receptor (GPCR) signaling pathway (6). It Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 has been reported that b-arrestin1 is also involved in autoimmune Yueyang Road, Shanghai 200031, China. E-mail addresses: [email protected] (B.S.) and [email protected] (G.P.) diseases such as experimental autoimmune encephalomyelitis and rheumatoid arthritis (7, 8). On the one hand, b-arrestin1 positively The online version of this article contains supplemental material. + 2 2 regulates CD4 T cell survival and homeostasis by promoting Bcl- Abbreviations used in this article: AIM2, absent in melanoma 2; Arrb1 / , b-arrestin1 deficient; ASC, apoptosis-associated speck-like protein containing 2 expression. On the other hand, b-arrestin1 also regulates Th17 a CARD; BMDC, bone marrow–derived dendritic cell; v-3 FA, omega-3 fatty acid; cell differentiation through scaffolding the interaction of JAK1 LDH, lactate dehydrogenase; MSU, monosodium urate; NLR, nucleotide-binding domain and leucine-rich repeat containing; NLRC4, NLR family CARD domain– and STAT3, thereby promoting STAT3 activation. In the pres- containing protein 4; NLRP3, NLR family pyrin domain–containing 3; NMDA, ent study, we found that in b-arrestin1–deficient peritoneal N-methyl-D-aspartate; poly(dA:dT), poly(deoxyadenylic-thymidylic) acid; WT, macrophages, NLRP3 and NLRC4 inflammasome activation were wild-type. strikingly dampened. In contrast, b-arrestin1 deficiency had Copyright Ó 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$25.00 no effect on AIM2 inflammasome activation. Moreover, with www.jimmunol.org/cgi/doi/10.4049/jimmunol.1401989 1868 REGULATION OF INFLAMMASOME ACTIVATION BY b-arrestin1 a crosslinking assay and immunofluorescence assay, b-arrestin1 was various combinations of plasmids. At 24 h after the transfection, the cell found to promote NLRP3- and NLRC4-induced ASC pyroptosome lysates were prepared in lysis buffer and incubated with the indicated Ab formation. Further mechanistic study revealed that b-arrestin1 together with protein A/G Plus–agarose immunoprecipitation reagent (Santa Cruz Biotechnology) at 4˚C for 3 h or overnight. After three washes, specifically interacted with NLRP3 and NLRC4 and enhanced their the immunoprecipitates were boiled in SDS sample buffer for 10 min self-oligomerization. In vivo, b-arrestin1 was involved in a mono- and analyzed by immunoblot. sodium urate (MSU)–induced peritonitis model by promoting IL-1b For interaction of NLRs and b-arrestin1, NLRP3, NLRC4, and NLRP12 production and neutrophil influx. During Salmonella typhimurium were cloned into p3xFLAG-CMV-10 expression vector (Sigma-Aldrich) to express 3xFLAG-NLRs. 3xFLAG peptide (Sigma-Aldrich) was used infection, which causes severe inflammation through NLRC4 according to the manufacturer’s recommendations. In short,
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