Activation of Inflammasomes Requires Intracellular Redistribution of the Apoptotic Speck-Like Protein Containing a Caspase Recruitment Domain

被引:203
作者
Bryan, Nicole B. [1 ,2 ]
Dorfleutner, Andrea [1 ]
Rojanasakul, Yon [3 ]
Stehlik, Christian [1 ]
机构
[1] Northwestern Univ, Div Rheumatol, Dept Med, Feinberg Sch Med, Chicago, IL 60611 USA
[2] W Virginia Univ, Hlth Sci Ctr, Program Canc Cell Biol, Morgantown, WV 26506 USA
[3] W Virginia Univ, Dept Pharmaceut Sci, Sch Pharm, Hlth Sci Ctr, Morgantown, WV 26506 USA
基金
美国国家卫生研究院;
关键词
NF-KAPPA-B; CELL-DEATH; NUCLEAR-LOCALIZATION; PYRIN DOMAIN; ENZYME ICE; ASC; INTERLEUKIN-1-BETA; CRYOPYRIN; REGULATOR; BINDING;
D O I
10.4049/jimmunol.0802367
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Activation of caspase I is essential for the maturation and release of IL-1 beta and IL-18 and occurs in multiprotein complexes, referred to as inflammasomes. The apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is the essential adaptor protein for recruiting pro-caspase I into inflammasomes, and consistently gene ablation of ASC abolishes caspase 1 activation and secretion of IL-1 beta and IL-18. However, distribution of endogenous ASC has not yet been examined in detail. In the present study, we demonstrated that ASC localized primarily to the nucleus in resting human monocytes/macrophages. Upon pathogen infection, ASC rapidly redistributed to the cytosol, followed by assembly of perinuclear aggregates, containing several inflammasome components, including caspase I and Nod-like receptors. Prevention of ASC cytosolic redistribution completely abolished pathogen-induced inflammasome activity, which affirmed that cytosolic localization or ASC is essential for inflammasome function. Thus, our study characterized a novel mechanism of inflammasome regulation in host defense. The Journal of Immunology, 2009, 182: 3173-3182.
引用
收藏
页码:3173 / 3182
页数:10
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