Guanylate binding proteins promote caspase-11-dependent pyroptosis in response to cytoplasmic LPS
Guanylate binding proteins promote caspase-11-dependent pyroptosis in response to cytoplasmic LPS
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DOI：
10.1073/pnas.1321700111
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发表时间：
2014-04-22
影响因子：
11.1
通讯作者：
Coers, Joern
中科院分区：
文献类型：
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作者：
Pilla, Danielle M.;Hagar, Jon A.;Coers, Joern
干扰素受体信号转导诱导细胞自主免疫，抵抗细胞内细菌感染。在这里，我们证明了干扰素诱导的鸟苷结合蛋白(GBP)蛋白刺激caspase-11依赖的细胞自主免疫反应胞浆内毒素。感染革兰氏阴性细菌嗜肺军团菌的干扰素激活的巨噬细胞会触发依赖于caspase-11的下垂。在干扰素激活的巨噬细胞中快速诱导下垂需要一簇干扰素诱导的小鼠3号染色体上编码的GBP蛋白(GBP(Chr3))。SdhA L.嗜肺突变株类似地依赖于Gbpchr3，这表明这些GBP蛋白在检测进入胞浆的细菌方面发挥了作用。沙门氏菌来源的胞质内毒素。或大肠杆菌最近被证明可触发caspase-11的激活和下垂，但内毒素的细胞质感受器和caspase-11炎症体的成分尚未确定。我们发现，嗜肺乳杆菌胞质来源的内毒素诱导依赖于caspase-11的下垂需要GBP(Chr3)蛋白。同样，在缺乏GBP(Chr3)的巨噬细胞中，从沙门氏菌中分离出的胞浆内毒素引起的下垂反应也被减弱。这些数据提示GBP(Chr3)蛋白在检测胞浆内毒素和激活非典型炎症体中起作用。
IFN receptor signaling induces cell-autonomous immunity to infections with intracellular bacterial pathogens. Here, we demonstrate that IFN-inducible guanylate binding protein (Gbp) proteins stimulate caspase-11-dependent, cell-autonomous immunity in response to cytoplasmic LPS. Caspase-11-dependent pyroptosis is triggered in IFN-activated macrophages infected with the Gram-negative bacterial pathogen Legionella pneumophila. The rapid induction of pyroptosis in IFN-activated macrophages required a cluster of IFN-inducible Gbp proteins encoded on mouse chromosome 3 (Gbp(chr3)). Induction of pyroptosis in naive macrophages by infections with the cytosol-invading.sdhA L. pneumophila mutant was similarly dependent on Gbpchr3, suggesting that these Gbp proteins play a role in the detection of bacteria accessing the cytosol. Cytoplasmic LPS derived from Salmonella ssp. or Escherichia coli has recently been shown to trigger caspase-11 activation and pyroptosis, but the cytoplasmic sensor for LPS and components of the caspase-11 inflammasome are not yet defined. We found that the induction of caspase-11-dependent pyroptosis by cytoplasmic L. pneumophila-derived LPS required Gbp(chr3) proteins. Similarly, pyroptosis induced by cytoplasmic LPS isolated from Salmonella was diminished in Gbp(chr3)-deficient macrophages. These data suggest a role for Gbp(chr3) proteins in the detection of cytoplasmic LPS and the activation of the noncanonical inflammasome.