PDF(Pubmed)
Abstract：
Pathogen infection of host cells triggers an inflammatory cell death termed pyroptosis via activation of inflammatory caspases. However, blockade of immune signaling kinases by the Yersinia virulence factor YopJ triggers cell death involving both apoptotic caspase-8 and pyroptotic caspase-1. While caspase-1 is normally activated within inflammasomes, Yersinia-induced caspase-1 activation is independent of known inflammasome components. We report that caspase-8 is an essential initiator, while caspase-1 is an essential amplifier of its own activation through two feed-forward loops involving caspase-1 auto-processing and caspase-1-dependent activation of gasdermin D and NLPR3. Notably, while Yersinia-induced caspase-1 activation and cell death are inflammasome-independent, IL-1β release requires NLPR3 inflammasome activation. Mechanistically, caspase-8 is rapidly activated within multiple foci throughout the cell, followed by assembly of a canonical inflammasome speck, indicating that caspase-8 and canonical inflammasome complex assemblies are kinetically and spatially distinct. Our findings reveal that functionally interconnected but distinct death complexes mediate pyroptosis and IL-1β release in response to pathogen blockade of immune signaling.
摘要：
宿主细胞的病原体感染通过炎性半胱天冬酶的激活引发称为焦亡的炎性细胞死亡。然而,耶尔森氏菌毒力因子YopJ对免疫信号激酶的阻断引发细胞死亡，涉及凋亡的caspase-8和焦转的caspase-1。虽然caspase-1通常在炎症体内被激活，耶尔森氏菌诱导的caspase-1激活与已知的炎性体成分无关。我们报道caspase-8是一种重要的引发剂，而caspase-1是通过两个前馈环激活其自身激活的必需放大器，这两个前馈环涉及caspase-1自动加工和caspase-1依赖性GasderminD和NLPR3的激活。值得注意的是,而耶尔森氏菌诱导的caspase-1激活和细胞死亡是不依赖炎性体的，IL-1β释放需要NLPR3炎性体激活。机械上,caspase-8在整个细胞的多个病灶内迅速激活，然后是一个典型的炎症斑点，表明caspase-8和典型的炎性体复合物组件在动力学和空间上是不同的。我们的发现表明，功能上相互关联但不同的死亡复合物介导了对病原体阻断免疫信号的反应，从而介导了焦亡和IL-1β的释放。
