Yersinia enterocolitica YopT and Clostridium difficile toxin B induce expression of GILZ in epithelial cells.
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.
Interfaculty Institute of Microbiology and Infection Medicine, Eberhard Karls University of Tübingen, Tübingen, Germany.
Martin
M
Köberle
David
D
Göppel
Tanja
T
Grandl
Peer
P
Gaentzsch
Birgit
B
Manncke
Susanne
S
Berchtold
Steffen
S
Müller
Bernhard
B
Lüscher
Marie-Liesse
ML
Asselin-Labat
Marc
M
Pallardy
Isabel
I
Sorg
Simon
S
Langer
Holger
H
Barth
Robert
R
Zumbihl
Ingo B
IB
Autenrieth
Erwin
E
Bohn
D017209:Apoptosis; D001426:Bacterial Proteins / Q000378:metabolism*; D001427:Bacterial Toxins / Q000378:metabolism*; D001483:Base Sequence; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D024721:E-Box Elements; D004847:Epithelial Cells / Q000378:metabolism* / Q000382:microbiology; D015870:Gene Expression; D020869:Gene Expression Profiling; D006367:HeLa Cells; D006801:Humans; D007249:Inflammation / Q000235:genetics; D018836:Inflammation Mediators / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D051720:Upstream Stimulatory Factors / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D001426:Bacterial Proteins; D001427:Bacterial Toxins; D018836:Inflammation Mediators; D016328:NF-kappa B; C404226:TSC22D3 protein, human; D014157:Transcription Factors; C497181:USF1 protein, human; C497184:USF2 protein, human; D051720:Upstream Stimulatory Factors; C116117:YopT protein, Yersinia; C031815:toxB protein, Clostridium difficile; D020928:Mitogen-Activated Protein Kinases; D003546:Cysteine Endopeptidases; D020741:rho GTP-Binding Proteins