AIM2炎性小体通过核膜完整性的药理学破坏而被激活。
AIM2 inflammasome is activated by pharmacological disruption of nuclear envelope integrity.
作者信息
Di Micco Antonia, Frera Gianluca, Lugrin Jérôme, Jamilloux Yvan, Hsu Erh-Ting, Tardivel Aubry, De Gassart Aude, Zaffalon Léa, Bujisic Bojan, Siegert Stefanie, Quadroni Manfredo, Broz Petr, Henry Thomas, Hrycyna Christine A, Martinon Fabio
机构信息
Department of Biochemistry, University of Lausanne, Epalinges 1066, Switzerland;
Department of Biochemistry, University of Lausanne, Epalinges 1066, Switzerland; INSERM, U1111, Center for Infectiology Research, Lyon 69007, France;
出版信息
Proc Natl Acad Sci U S A. 2016 Aug 9;113(32):E4671-80. doi: 10.1073/pnas.1602419113. Epub 2016 Jul 26.
Inflammasomes are critical sensors that convey cellular stress and pathogen presence to the immune system by activating inflammatory caspases and cytokines such as IL-1β. The nature of endogenous stress signals that activate inflammasomes remains unclear. Here we show that an inhibitor of the HIV aspartyl protease, Nelfinavir, triggers inflammasome formation and elicits an IL-1R-dependent inflammation in mice. We found that Nelfinavir impaired the maturation of lamin A, a structural component of the nuclear envelope, thereby promoting the release of DNA in the cytosol. Moreover, deficiency of the cytosolic DNA-sensor AIM2 impaired Nelfinavir-mediated inflammasome activation. These findings identify a pharmacologic activator of inflammasome and demonstrate the role of AIM2 in detecting endogenous DNA release upon perturbation of nuclear envelope integrity.
炎性小体是关键的传感器，通过激活炎性半胱天冬酶和细胞因子（如白细胞介素-1β）将细胞应激和病原体的存在传递给免疫系统。激活炎性小体的内源性应激信号的本质仍不清楚。在这里，我们表明，HIV天冬氨酸蛋白酶抑制剂奈非那韦可触发炎性小体形成，并在小鼠中引发白细胞介素-1受体依赖性炎症。我们发现，奈非那韦损害了核纤层蛋白A（核膜的一种结构成分）的成熟，从而促进了DNA在细胞质中的释放。此外，胞质DNA传感器AIM2的缺陷削弱了奈非那韦介导的炎性小体激活。这些发现确定了炎性小体的一种药理激活剂，并证明了AIM2在检测核膜完整性受到干扰时内源性DNA释放中的作用。
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