Cyclic-di-GMP and cyclic-di-AMP activate the NLRP3 inflammasome

被引:66
作者
Abdul-Sater, Ali A. [1 ]
Tattoli, Ivan [2 ]
Jin, Lei [3 ,4 ]
Grajkowski, Andrzej [5 ]
Levi, Assaf [6 ]
Koller, Beverly H. [7 ,8 ]
Allen, Irving C. [9 ,10 ]
Beaucage, Serge L. [5 ]
Fitzgerald, Katherine A. [11 ]
Ting, Jenny P. -Y. [9 ,10 ]
Cambier, John C. [3 ,4 ]
Girardin, Stephen E. [2 ]
Schindler, Christian [1 ,12 ]
机构
[1] Columbia Univ, Dept Microbiol & Immunol, New York, NY 10032 USA
[2] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON M5S 1A8, Canada
[3] Univ Colorado, Integrated Dept Immunol, Denver Sch Med, Denver, CO 80206 USA
[4] Natl Jewish Hlth, Denver, CO 80206 USA
[5] US FDA, Div Therapeut Prot, Ctr Drug Evaluat & Res, Bethesda, MD 20892 USA
[6] Univ Chicago, Dept Microbiol, Cummings Life Sci Ctr, Chicago, IL 60637 USA
[7] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA
[8] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA
[9] Univ N Carolina, Dept Microbiol Immunol, Chapel Hill, NC 27599 USA
[10] Univ N Carolina, Lineberger Comprehens Canc Ctr, Inst Inflammatory Dis, Chapel Hill, NC 27599 USA
[11] Univ Massachusetts, Sch Med, Div Infect Dis & Immunol, Worcester, MA 01605 USA
[12] Columbia Univ, Dept Med, New York, NY 10032 USA
关键词
inflammasome; cyclic-di-GMP; cyclic-di-AMP; PAMP; cytokines; NALP3; INFLAMMASOME; HOST-DEFENSE; DNA; IMMUNITY; RECOGNIZES; SUSCEPTIBILITY; CRYSTALS; BACTERIA; HEALTH; TOXINS;
D O I
10.1038/embor.2013.132
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The cyclic dinucleotides 3'-5'diadenylate (c-diAMP) and 3'-5' diguanylate (c-diGMP) are important bacterial second messengers that have recently been shown to stimulate the secretion of type I Interferons (IFN-Is) through the c-diGMP-binding protein MPYS/STING. Here, we show that physiologically relevant levels of cyclic dinucleotides also stimulate a robust secretion of IL-1 beta through the NLRP3 inflammasome. Intriguingly, this response is independent of MPYS/STING. Consistent with most NLRP3 inflammasome activators, the response to c-diGMP is dependent on the mobilization of potassium and calcium ions. However, in contrast to other NLRP3 inflammasome activators, this response is not associated with significant changes in mitochondrial potential or the generation of mitochondrial reactive oxygen species. Thus, cyclic dinucleotides activate the NLRP3 inflammasome through a unique pathway that could have evolved to detect pervasive bacterial pathogen-associated molecular patterns associated with intracellular infections.
引用
收藏
页码:900 / 906
页数:7
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