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Infection and Immunity, December 2009, p. 5583-5592, Vol. 77, No. 12
0019-9567/09/$08.00+0     doi:10.1128/IAI.00121-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Bacterial Toxins Induce Sustained mRNA Expression of the Silencing Transcription Factor klf2 via Inactivation of RhoA and Rhophilin 1{triangledown}

Kristina Dach, Josip Zovko, Michael Hogardt, Isabel Koch, Katrin van Erp, Jürgen Heesemann, and Reinhard Hoffmann*

Max von Pettenkofer-Institut, Department of Bacteriology, Pettenkoferstr. 9A, 80336 Munich, Germany

Received 2 February 2009/ Returned for modification 21 March 2009/ Accepted 17 September 2009

Yersiniae bearing the Yersinia virulence plasmid pYV impact the transcriptome of J774A.1 macrophage-like cells in two distinct ways: (i) by suppressing, in a Yersinia outer protein P (YopP)-dependent manner, the induction of inflammatory response genes and (ii) by mRNA induction of the silencing transcription factor klf2. Here we show that klf2 induction by Yersinia enterocolitica occurs in several cell lines of macrophage and squamous and upper gastrointestinal epithelial origin as well as in bone marrow-derived dendritic cells. Several strains of Pseudomonas aeruginosa and Staphylococcus aureus are equally effective as Y. enterocolitica in inducing klf2 expression. Screening of mutant strains or incubation with recombinant toxins identified the rho-inactivating toxins YopT from Yersinia spp., ExoS from Pseudomonas aeruginosa, EDIN-B from Staphylococcus aureus, and C3bot from Clostridium botulinum as bacterial inducers of klf2 mRNA. klf2 mRNA induction by these toxins does not require de novo protein synthesis. Serum response factor or actin depolymerization does not seem to be involved in regulating klf2 expression in response to bacterial infection. Instead, short hairpin RNA-mediated inactivation of RhoA and its effector rhophilin 1 is sufficient to induce long-term klf2 expression. Thus, bacteria exploit the RhoA-rhophilin signaling cascade to mediate sustained expression of the immunosuppressive transcription factor klf2.

* Corresponding author. Mailing address: Institute for Medical Microbiology, Immunology and Hygiene, Technical University Munich, Trogerstr. 30, 81675 Munich, Germany. Phone: 49-89-4140-4155. Fax: 49-89-4140-4933. E-mail: reinhard.hoffmann{at}lrz.tum.de

{triangledown} Published ahead of print on 28 September 2009.

Editor: J. B. Bliska

Infection and Immunity, December 2009, p. 5583-5592, Vol. 77, No. 12
0019-9567/09/$08.00+0     doi:10.1128/IAI.00121-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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