Main content area

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

Ge, Jianning, Xu, Hao, Li, Ting, Zhou, Yan, Zhang, Zhibin, Li, Shan, Liu, Liping, Shao, Feng
Proceedings of the National Academy of Sciences of the United States of America 2009 v.106 no.33 pp. 13725-13730
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
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.