Yersinia Outer Protein P of Yersinia enterocolitica Simultaneously Blocks the Nuclear Factor-κB Pathway and Exploits Lipopolysaccharide Signaling to Trigger Apoptosis in Macrophages

摘要

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-κB 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-κB activation and subsequently conferred apoptosis to J774A.1 macrophages. Thereby, YopP bound and inhibited the macrophage NF-κB-activating kinase IKKβ. YopP- and Yersinia- , but not Salmonella -induced apoptosis was specifically prevented by transient overexpression of NF-κB p65, giving evidence that YopP mediates cell death by disrupting the NF-κB 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-κB by YopP. This reflects a strategy of a bacterial pathogen that takes advantage of LPS, serving as cofactor, to impair the macrophage.