A Legionella type IV effector activates the NF-κB pathway by phosphorylating the IκB family of inhibitors
A Legionella type IV effector activates the NF-κB pathway by phosphorylating the IκB family of inhibitors
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DOI：
10.1073/pnas.0907200106
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发表时间：
2009-08-18
影响因子：
11.1
通讯作者：
Shao, Feng
中科院分区：
文献类型：
--
作者：
Ge, Jianning;Xu, Hao;Shao, Feng
NF-κ B在抵抗入侵微生物病原体的先天免疫防御反应中是至关重要的。肺巨噬细胞的嗜肺军团菌感染引起军团菌病，伴有肺炎症状。一组参与炎症和抗凋亡的NF-κ B控制的基因在巨噬细胞中被L.嗜肺军团菌以军团菌Dot/Icm IV型分泌系统依赖性方式感染。在筛选的大约100个Dot/Icm底物中，我们确定LegK 1为唯一的军团菌蛋白，其具有高度有效的NF-κ B刺激活性。LegK 1不影响MAPK和IFN途径。LegK 1激活NF-κ B通路需要其真核样Ser/Thr激酶活性，并且不依赖于NF-κ B通路的上游组分，包括TRAF、NIK、MEKK 3和TAK 1。无细胞重建显示，在IKK α和IKK β不存在的情况下，LegK 1刺激NF-κ B活化，并且LegK 1在体外和细胞中有效地磷酸化Ser-32和Ser-36上的I κ B α。LegK 1似乎模拟宿主IKK，因为LegK 1还直接磷酸化其他I κ B家族抑制剂，包括非经典NF-κ B途径中的p100。LegK 1对p100的磷酸化导致其成熟为p52。因此，LegK 1是一种细菌效应子，直接激活宿主NF-κ B信号传导，并可能在调节L.嗜肺菌感染
NF-kappa B is critical in innate immune defense responses against invading microbial pathogens. Legionella pneumophila infection of lung macrophages causes Legionnaire's disease with pneumonia symptoms. A set of NF-kappa B-controlled genes involved in inflammation and anti-apoptosis are up-regulated in macrophages upon L. pneumophila infection in a Legionella Dot/Icm type IV secretion system-dependent manner. Among approximate to 100 Dot/Icm substrates screened, we identified LegK1 as the sole Legionella protein that harbors a highly potent NF-kappa B-stimulating activity. LegK1 does not affect MAPK and IFN pathways. Activation of the NF-kappa B pathway by LegK1 requires its eukaryotic-like Ser/Thr kinase activity and is independent of upstream components in the NF-kappa B pathway, including TRAFs, NIK, MEKK3, and TAK1. Cell-free reconstitution revealed that LegK1 stimulated NF-kappa B activation in the absence of IKK alpha and IKK beta, and LegK1 efficiently phosphorylated I kappa B alpha on Ser-32 and Ser-36 both in vitro and in cells. LegK1 seems to mimic the host IKK as LegK1 also directly phosphorylated other I kappa B family of inhibitors including p100 in the noncanonical NF-kappa B pathway. Phosphorylation of p100 by LegK1 led to its maturation into p52. Thus, LegK1 is a bacterial effector that directly activates the host NF-kappa B signaling and likely plays important roles in modulating macrophage defense or inflammatory responses during L. pneumophila infection.