Yersinia outer protein P of Yersinia enterocolitica simultaneously blocks the nuclear factor-kappa B pathway and exploits lipopolysaccharide signaling to trigger apoptosis in macrophages.
Exposure of macrophages to bacteria or LPS mediates activation of signaling pathways that induce expression of self defense-related genes. Pathogenic Yersinia species impair activation of transcription factor NF-kappaB and trigger apoptosis in macrophages. In this study, we dissected the mechanism of apoptosis induction by Yersinia. Selectively, Yersinia enterocolitica strains producing the effector protein Yersinia outer protein P (YopP) hampered NF-kappaB activation and subsequently conferred apoptosis to J774A.1 macrophages. Thereby, YopP bound and inhibited the macrophage NF-kappaB-activating kinase IKKbeta. YopP- and Yersinia-, but not Salmonella-induced apoptosis was specifically prevented by transient overexpression of NF-kappaB p65, giving evidence that YopP mediates cell death by disrupting the NF-kappaB signaling pathway. Transfection of J774A.1 macrophages with YopP induced a moderate, but significant degree of apoptosis (40-50% of transfected cells). This effect was strongly enhanced by additional initiation of LPS signaling (80-90%), indicating a synergism between LPS-induced signal transduction and inhibition of NF-kappaB by YopP. This reflects a strategy of a bacterial pathogen that takes advantage of LPS, serving as cofactor, to impair the macrophage.
Ruckdeschel
K
K
Max von Pettenkofer-Institut für Hygiene und Medizinische Mikrobiologie, München, Germany.
Mannel
O
O
Richter
K
K
Jacobi
C A
CA
Trülzsch
K
K
Rouot
B
B
Heesemann
J
J
D018829:Adhesins, Bacterial / Q000276:immunology* / Q000378:metabolism / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D004789:Enzyme Activation / Q000276:immunology; D020672:I-kappa B Proteins; D007166:Immunosuppressive Agents / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology*; D008264:Macrophages / Q000166:cytology / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology*; D012486:Salmonella typhimurium / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D051996:Transcription Factor RelA; D015008:Yersinia enterocolitica / Q000276:immunology*
D018829:Adhesins, Bacterial; D004268:DNA-Binding Proteins; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; D016328:NF-kappa B; D051996:Transcription Factor RelA; C064832:YadA protein, Yersinia