Bacterial toxins induce sustained mRNA expression of the silencing transcription factor klf2 via inactivation of RhoA and Rhophilin 1.
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.
Department of Bacteriology, Max von Pettenkofer-Institut, Pettenkoferstr 9A, 80336 Munich, Germany.
Kristina
K
Dach
Josip
J
Zovko
Michael
M
Hogardt
Isabel
I
Koch
Katrin
K
van Erp
Jürgen
J
Heesemann
Reinhard
R
Hoffmann
D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors*; D000818:Animals; D001427:Bacterial Toxins / Q000633:toxicity*; D002460:Cell Line; D003014:Clostridium botulinum / Q000472:pathogenicity; D005786:Gene Expression Regulation; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000096:biosynthesis*; D051379:Mice; D011550:Pseudomonas aeruginosa / Q000472:pathogenicity; D012333:RNA, Messenger / Q000096:biosynthesis*; D013211:Staphylococcus aureus / Q000472:pathogenicity; D015008:Yersinia enterocolitica / Q000472:pathogenicity; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors*
D048868:Adaptor Proteins, Signal Transducing; D001427:Bacterial Toxins; C096161:KLF2 protein, human; D051741:Kruppel-Like Transcription Factors; D012333:RNA, Messenger; C097916:rhophilin; D020742:rhoA GTP-Binding Protein