title: Systematic analysis of cyclic di-GMP signalling enzymes and their role in biofilm formation and virulence in Yersinia pestis.
abstract: Cyclic di-GMP (c-di-GMP) is a signalling molecule that governs the transition between planktonic and biofilm states. Previously, we showed that the diguanylate cyclase HmsT and the putative c-di-GMP phosphodiesterase HmsP inversely regulate biofilm formation through control of HmsHFRS-dependent poly-β-1,6-N-acetylglucosamine synthesis. Here, we systematically examine the functionality of the genes encoding putative c-di-GMP metabolic enzymes in Yersinia pestis. We determine that, in addition to hmsT and hmsP, only the gene y3730 encodes a functional enzyme capable of synthesizing c-di-GMP. The seven remaining genes are pseudogenes or encode proteins that do not function catalytically or are not expressed. Furthermore, we show that HmsP has c-di-GMP-specific phosphodiesterase activity. We report that a mutant incapable of c-di-GMP synthesis is unaffected in virulence in plague mouse models. Conversely, an hmsP mutant, unable to degrade c-di-GMP, is defective in virulence by a subcutaneous route of infection due to poly-β-1,6-N-acetylglucosamine overproduction. This suggests that c-di-GMP signalling is not only dispensable but deleterious for Y. pestis virulence. Our results show that a key event in the evolution of Y. pestis from the ancestral Yersinia pseudotuberculosis was a significant reduction in the complexity of its c-di-GMP signalling network likely resulting from the different disease cycles of these human pathogens.
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, KY, USA. bobrov@uky.edu
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Bobrov
authors.forename: Olga
authors.initials: O
authors.lastname: Kirillina
authors.forename: Dmitri A
authors.initials: DA
authors.lastname: Ryjenkov
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Waters
authors.forename: Paul A
authors.initials: PA
authors.lastname: Price
authors.forename: Jacqueline D
authors.initials: JD
authors.lastname: Fetherston
authors.forename: Dietrich
authors.initials: D
authors.lastname: Mack
authors.forename: William E
authors.initials: WE
authors.lastname: Goldman
authors.forename: Mark
authors.initials: M
authors.lastname: Gomelsky
authors.forename: Robert D
authors.initials: RD
authors.lastname: Perry
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000378:metabolism*; D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism*; D018441:Biofilms / Q000254:growth & development*; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D010930:Plague / Q000382:microbiology / Q000473:pathology; D015398:Signal Transduction; D014774:Virulence; D037521:Virulence Factors / Q000378:metabolism*; D015010:Yersinia pestis / Q000201:enzymology / Q000378:metabolism / Q000472:pathogenicity*
chemical_list: D001426:Bacterial Proteins; C122178:HMST protein, Yersinia pestis; D037521:Virulence Factors; C062025:bis(3',5')-cyclic diguanylic acid; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D006152:Cyclic GMP