A Legionella type IV effector activates the NF-kappaB pathway by phosphorylating the IkappaB family of inhibitors.
NF-kappaB 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-kappaB-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 approximately 100 Dot/Icm substrates screened, we identified LegK1 as the sole Legionella protein that harbors a highly potent NF-kappaB-stimulating activity. LegK1 does not affect MAPK and IFN pathways. Activation of the NF-kappaB pathway by LegK1 requires its eukaryotic-like Ser/Thr kinase activity and is independent of upstream components in the NF-kappaB pathway, including TRAFs, NIK, MEKK3, and TAK1. Cell-free reconstitution revealed that LegK1 stimulated NF-kappaB activation in the absence of IKKalpha and IKKbeta, and LegK1 efficiently phosphorylated IkappaBalpha 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 IkappaB family of inhibitors including p100 in the noncanonical NF-kappaB pathway. Phosphorylation of p100 by LegK1 led to its maturation into p52. Thus, LegK1 is a bacterial effector that directly activates the host NF-kappaB signaling and likely plays important roles in modulating macrophage defense or inflammatory responses during L. pneumophila infection.
Ge
Jianning
J
College of Life Sciences, Beijing Normal University, Beijing 100875, China.
Xu
Hao
H
Li
Ting
T
Zhou
Yan
Y
Zhang
Zhibin
Z
Li
Shan
S
Liu
Liping
L
Shao
Feng
F
D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D006367:HeLa Cells; D006801:Humans; D020672:I-kappa B Proteins / Q000737:chemistry*; D016952:Legionella pneumophila / Q000378:metabolism; D007877:Legionnaires' Disease / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction
D020672:I-kappa B Proteins; D016328:NF-kappa B