Yersinia outer protein P suppresses TGF-beta-activated kinase-1 activity to impair innate immune signaling in Yersinia enterocolitica-infected cells.
Pathogenic Yersinia spp. use a panel of virulence proteins that antagonize signal transduction processes in infected cells to undermine host defense mechanisms. One of these proteins, Yersinia enterocolitica outer protein P (YopP), down-regulates the NF-kappaB and MAPK signaling pathways, which suppresses the proinflammatory host immune response. In this study, we explored the mechanism by which YopP succeeds to simultaneously disrupt several of these key signaling pathways of innate immunity. Our data show that YopP operates upstream of its characterized eukaryotic binding partner IkappaB kinase-beta to shut down the NF-kappaB signaling cascade. Accordingly, YopP efficiently impaired the activities of TGF-beta-activated kinase-1 (TAK1) in infected cells. TAK1 is an important activator of the IkappaB kinase complex in the TLR signaling cascade. The repression of TAK1 activities correlated with reduced activation of NF-kappaB- as well as AP-1-dependent reporter gene expression in Yersinia-infected murine macrophages. This suggests that the impairment of the TAK1 enzymatic activities by Yersinia critically contributes to down-regulate activation of NF-kappaB and of MAPK members in infected host cells. The inhibition of TAK1 potentially results from the blockade of signaling events that control TAK1 induction. This process could involve the attenuation of ubiquitination of the upstream signal transmitter TNFR-associated factor-6. Together, these results indicate that, by silencing the TAK1 signaling complex, Yersinia counteracts the induction of several conserved signaling pathways of innate immunity, which aids the bacterium in subverting the host immune response.
Haase
Rudolf
R
Max von Pettenkofer-Institute for Hygiene and Medical Microbiology, Munich, Germany.
Richter
Kathleen
K
Pfaffinger
Gudrun
G
Courtois
Gilles
G
Ruckdeschel
Klaus
K
D000818:Animals; D001426:Bacterial Proteins / Q000502:physiology*; D002460:Cell Line; D006801:Humans; D007113:Immunity, Innate; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000276:immunology*; D008264:Macrophages / Q000382:microbiology; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D018808:Transcription Factor AP-1; D015009:Yersinia Infections / Q000276:immunology* / Q000378:metabolism; D015008:Yersinia enterocolitica / Q000472:pathogenicity; D000099151:MAP Kinase Kinase Kinase 7
D001426:Bacterial Proteins; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D000099151:MAP Kinase Kinase Kinase 7; C109227:YopP protein, Yersinia