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A Legionella type IV effector activates the NF-κB pathway by phosphorylating the IκB family of inhibitors

机译:军团菌IV型效应子通过使抑制剂的IκB家族磷酸化来激活NF-κB途径

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摘要

NF-κB 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-κB-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 ≈100 Dot/Icm substrates screened, we identified LegK1 as the sole Legionella protein that harbors a highly potent NF-κB-stimulating activity. LegK1 does not affect MAPK and IFN pathways. Activation of the NF-κB pathway by LegK1 requires its eukaryotic-like Ser/Thr kinase activity and is independent of upstream components in the NF-κB pathway, including TRAFs, NIK, MEKK3, and TAK1. Cell-free reconstitution revealed that LegK1 stimulated NF-κB activation in the absence of IKKα and IKKβ, and LegK1 efficiently phosphorylated IκBα 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 IκB family of inhibitors including p100 in the noncanonical NF-κB pathway. Phosphorylation of p100 by LegK1 led to its maturation into p52. Thus, LegK1 is a bacterial effector that directly activates the host NF-κB signaling and likely plays important roles in modulating macrophage defense or inflammatory responses during L. pneumophila infection.
机译:NF-κB在针对入侵微生物病原体的先天免疫防御反应中至关重要。肺巨噬细胞嗜肺军团菌感染会导致军团病并伴有肺炎症状。一组与炎症和抗凋亡有关的NF-κB控制基因在嗜肺乳杆菌感染后以军团菌点/ Icm IV型分泌系统依赖性方式上调。在被筛选的约100个Dot / Icm底物中,我们确定LegK1是唯一具有高强度NF-κB刺激活性的军团菌蛋白。 LegK1不影响MAPK和IFN途径。 LegK1激活NF-κB通路需要其真核样Ser / Thr激酶活性,并且独立于NF-κB通路中的上游成分,包括TRAFs,NIK,MEKK3和TAK1。无细胞重建显示,在不存在IKKα和IKKβ的情况下,LegK1刺激NF-κB活化,并且LegK1在体外和细胞中均有效地磷酸化了Ser-32和Ser-36上的IκBα。 LegK1似乎模仿宿主IKK,因为LegK1还直接磷酸化其他IκB抑制剂家族,包括非规范NF-κB途径中的p100。 LegK1使p100磷酸化,使其成熟为p52。因此,LegK1是一种细菌效应子,可直接激活宿主NF-κB信号传导,并可能在调节嗜肺乳杆菌感染期间的巨噬细胞防御或炎症反应中发挥重要作用。

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