Preventing bacterial DNA release and absent in melanoma 2 inflammasome activation by a Legionella effector functioning in membrane trafficking
Preventing bacterial DNA release and absent in melanoma 2 inflammasome activation by a Legionella effector functioning in membrane trafficking
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DOI：
10.1073/pnas.1117490109
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发表时间：
2012-04-17
影响因子：
11.1
通讯作者：
Shao, Feng
中科院分区：
文献类型：
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作者：
Ge, Jianning;Gong, Yi-Nan;Shao, Feng
嗜肺军团菌（Legionella pneumophila）是军团菌肺炎的病原体，存在于一种独特的空泡结构中，称为含军团菌空泡（Legionella-containing vacuole，LCV）。LCV抵抗与溶酶体的融合，并允许宿主巨噬细胞中的有效细菌复制，这需要Dot/Icm型IVB分泌系统。Dot/icm易位效应子SdhA对L.嗜肺菌细胞内生长和功能，以防止宿主细胞死亡。在这里，我们表明，SdhA的情况下导致升高的半胱天冬酶-1激活和IL-1 β分泌以及巨噬细胞焦亡在军团菌感染。这些炎性小体激活表型独立于已建立的鞭毛蛋白-NAIP 5-NLRC 4轴，但依赖于DNA敏感的AIM 2炎性小体。我们进一步证明，军团菌DNA被释放到巨噬细胞胞质溶胶中，这种影响被显着夸大了SdhA的情况下。SdhA具有防止AIM 2炎性小体激活所需的功能性高尔基体靶向GRIP结构域。异位表达的SdhA形成了独特的环形膜结构，进一步表明在膜运输和维持LCV膜完整性的作用。我们的数据共同表明一个可能的联系，介导的功能SdhA，LCV贩运/成熟和抑制宿主先天免疫检测之间。
Legionella pneumophila, the causative agent of Legionnaires' pneumonia, resides in a distinct vacuole structure called Legionella-containing vacuole (LCV). The LCV resists fusion with the lysosome and permits efficient bacterial replication in host macrophages, which requires a Dot/Icm type IVB secretion system. Dot/icm-translocated effector SdhA is critical for L. pneumophila intracellular growth and functions to prevent host cell death. Here, we show that the absence of SdhA resulted in elevated caspase-1 activation and IL-1 beta secretion as well as macrophage pyroptosis during Legionella infection. These inflammasome activation phenotypes were independent of the established flagellin-NAIP5-NLRC4 axis, but relied on the DNA-sensing AIM2 inflammasome. We further demonstrate that Legionella DNA was released into macrophage cytosol, and this effect was significantly exaggerated by the absence of SdhA. SdhA bears a functional Golgi-targeting GRIP domain that is required for preventing AIM2 inflammasome activation. Ectopically expressed SdhA formed a unique ring-shape membrane structure, further indicating a role in membrane trafficking and maintaining LCV membrane integrity. Our data together suggest a possible link, mediated by the function of SdhA, between LCV trafficking/maturation and suppression of host innate immune detection.