Yersinia enterocolitica YopT and Clostridium difficile toxin B induce expression of GILZ in epithelial cells

• Published in: PloS one Vol. 7; no. 7; p. e40730
• Main Authors: Köberle, Martin, Göppel, David, Grandl, Tanja, Gaentzsch, Peer, Manncke, Birgit, Berchtold, Susanne, Müller, Steffen, Lüscher, Bernhard, Asselin-Labat, Marie-Liesse, Pallardy, Marc, Sorg, Isabel, Langer, Simon, Barth, Holger, Zumbihl, Robert, Autenrieth, Ingo B, Bohn, Erwin
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 09.07.2012; Public Library of Science (PLoS)
• Subjects: Activation; Anti-inflammatory agents; Antigens; Apoptosis; Bacteria; Bacterial Proteins - metabolism; Bacterial Toxins - metabolism; Base Sequence; Binding sites; Biology; c-Myc protein; Cysteine Endopeptidases - metabolism; Cytokines; Deactivation; Dendritic cells; Deprivation; Dexamethasone; DNA binding proteins; E-Box Elements; Epithelial cells; Epithelial Cells - metabolism; Epithelial Cells - microbiology; Experiments; Flow cytometry; G proteins; Gene Expression; Gene Expression Profiling; Glucocorticoids; Guanosine triphosphatases; Guanosinetriphosphatase; Health aspects; HeLa Cells; Humans; Inactivation; Infection; Infections; Inflammation; Inflammation - genetics; Inflammation Mediators - metabolism; Interleukin 10; Interleukin 2; Leucine; Leucine zipper proteins; Life Sciences; MAP kinase; Medical research; Medicine; Mitogen-Activated Protein Kinases - metabolism; Myc protein; NF-kappa B - metabolism; Promoter Regions, Genetic; Proteases; Protein expression; Proteins; rho GTP-Binding Proteins - metabolism; RhoA protein; RNA; Signal Transduction; Signaling; Toxicology; Toxin B; Toxins; Transcription; Transcription Factors - genetics; Transcription, Genetic; Transcriptional Activation; Upstream stimulating factor 1; Upstream stimulating factor 2; Upstream stimulatory factor; Upstream Stimulatory Factors - metabolism; Yersinia; Yersinia enterocolitica; Aachen Germany; France; Germany; INVASIN PROTEIN; VIRULENCE PLASMID; DENDRITIC CELLS; INDUCED LEUCINE-ZIPPER; PROTECTS T-LYMPHOCYTES; SIGNALING PATHWAY; BINDING PROTEINS; GENE-PRODUCT RHOB; THYMOCYTE APOPTOSIS; NF-KAPPA-B
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0040730

Glucocorticoid induced-leucine zipper (GILZ) has been shown to be induced in cells by different stimuli such as glucocorticoids, IL-10 or deprivation of IL-2. GILZ has anti-inflammatory properties and may be involved in signalling modulating apoptosis. Herein we demonstrate that wildtype Yersinia enterocolitica which carry the pYV plasmid upregulated GILZ mRNA levels and protein expression in epithelial cells. Infection of HeLa cells with different Yersinia mutant strains revealed that the protease activity of YopT, which cleaves the membrane-bound form of Rho GTPases was sufficient to induce GILZ expression. Similarly, Clostridium difficile toxin B, another bacterial inhibitor of Rho GTPases induced GILZ expression. YopT and toxin B both increased transcriptional activity of the GILZ promoter in HeLa cells. GILZ expression could not be linked to the inactivation of an individual Rho GTPase by these toxins. However, forced expression of RhoA and RhoB decreased basal GILZ promoter activity. Furthermore, MAPK activation proved necessary for profound GILZ induction by toxin B. Promoter studies and gel shift analyses defined binding of upstream stimulatory factor (USF) 1 and 2 to a canonical c-Myc binding site (E-box) in the GILZ promoter as a crucial step of its trans-activation. In addition we could show that USF-1 and USF-2 are essential for basal as well as toxin B induced GILZ expression. These findings define a novel way of GILZ promoter trans-activation mediated by bacterial toxins and differentiate it from those mediated by dexamethasone or deprivation of IL-2.