AIM2 inflammasome is activated by pharmacological disruption of nuclear envelope integrity
AIM2 inflammasome is activated by pharmacological disruption of nuclear envelope integrity
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DOI：
10.1073/pnas.1602419113
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发表时间：
2016-08-09
影响因子：
11.1
通讯作者：
Martinon, Fabio
中科院分区：
文献类型：
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作者：
Di Micco, Antonia;Frera, Gianluca;Martinon, Fabio
炎症小体是关键的传感器，通过激活炎症半胱天冬酶和细胞因子（例如 IL-1 beta）将细胞应激和病原体存在传递给免疫系统。激活炎症小体的内源性应激信号的性质仍不清楚。在这里，我们发现 HIV 天冬氨酰蛋白酶的抑制剂奈非那韦 (Nelfinavir) 会触发炎症小体的形成，并在小鼠中引发 IL-1R 依赖性炎症。我们发现奈非那韦损害了核膜结构成分核纤层蛋白 A 的成熟，从而促进细胞质中 DNA 的释放。此外，胞质 DNA 传感器 AIM2 的缺陷会损害奈非那韦介导的炎症小体激活。这些发现确定了炎症小体的药理学激活剂，并证明了 AIM2 在检测核膜完整性扰动时内源 DNA 释放中的作用。
Inflammasomes are critical sensors that convey cellular stress and pathogen presence to the immune system by activating inflammatory caspases and cytokines such as IL-1 beta. 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.