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

Author:
Ge, Jianning, Xu, Hao, Li, Ting, Zhou, Yan, Zhang, Zhibin, Li, Shan, Liu, Liping, Shao, Feng
Source:
Proceedings of the National Academy of Sciences of the United States of America 2009 v.106 no.33 pp. 13725-13730
ISSN:
0027-8424
Subject:
IKappaB kinase, Legionella pneumophila, Legionnaires' disease, gene expression regulation, genes, immune response, inflammation, macrophages, mitogen-activated protein kinase, pathogens, phosphorylation, pneumonia, transcription factor NF-kappa B, type IV secretion system
Abstract:
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.
Agid:
2365681