Yersinia pseudotuberculosis Effector YopJ Subverts the Nod2/RICK/TAK1 Pathway and Activates Caspase-1 to Induce Intestinal Barrier Dysfunction

• Published in: Cell host & microbe 2012-04, Vol.11 (4), p.337-351
• Main Authors: Meinzer, Ulrich, Barreau, Frederick, Esmiol-Welterlin, Sophie, Jung, Camille, Villard, Claude, Léger, Thibaut, Ben-Mkaddem, Sanah, Berrebi, Dominique, Dussaillant, Monique, Alnabhani, Ziad, Roy, Maryline, Bonacorsi, Stéphane, Wolf-Watz, Hans, Perroy, Julie, Ollendorff, Vincent, Hugot, Jean-Pierre
• Format: Article
• Language: English
• Subjects: Animals; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Biochemistry, Molecular Biology; Caspase 1 - genetics; Caspase 1 - metabolism; Cell Line; Female; Humans; Intestines - enzymology; Intestines - metabolism; Intestines - microbiology; Life Sciences; Male; MAP Kinase Kinase Kinases - genetics; MAP Kinase Kinase Kinases - metabolism; Mice; Mice, Inbred C57BL; Nod2 Signaling Adaptor Protein - genetics; Nod2 Signaling Adaptor Protein - metabolism; Receptor-Interacting Protein Serine-Threonine Kinase 2 - genetics; Receptor-Interacting Protein Serine-Threonine Kinase 2 - metabolism; Signal Transduction; Yersinia pseudotuberculosis - genetics; Yersinia pseudotuberculosis - metabolism; Yersinia pseudotuberculosis Infections - enzymology; Yersinia pseudotuberculosis Infections - genetics; Yersinia pseudotuberculosis Infections - metabolism; Yersinia pseudotuberculosis Infections - microbiology
• ISSN: 1931-3128; 1934-6069; 1934-6069
• DOI: 10.1016/j.chom.2012.02.009

Yersinia pseudotuberculosis is an enteropathogenic bacteria that disrupts the intestinal barrier and invades its host through gut-associated lymphoid tissue and Peyer's patches (PP). We show that the Y. pseudotuberculosis effector YopJ induces intestinal barrier dysfunction by subverting signaling of the innate immune receptor Nod2, a phenotype that can be reversed by pretreating with the Nod2 ligand muramyl-dipeptide. YopJ, but not the catalytically inactive mutant YopJC172A, acetylates critical sites in the activation loops of the RICK and TAK1 kinases, which are central mediators of Nod2 signaling, and decreases the affinity of Nod2 for RICK. Concomitantly, Nod2 interacts with and activates caspase-1, resulting in increased levels of IL-1β. Finally, IL-1β within PP plays an essential role in inducing intestinal barrier dysfunction. Thus, YopJ alters intestinal permeability and promotes the dissemination of Yersinia as well as commensal bacteria by exploiting the mucosal inflammatory response. ► The Yersinia effector YopJ increases gut permeability and bacterial translocation ► YopJ acetylates RICK and TAK1 and reduces the affinity of RICK for NOD2 ► As a result, NOD2 is free to interact and activate caspase-1 ► Caspase-1 promotes IL-1β secretion, resulting in epithelial barrier dysfunction