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Journal of Bacteriology, August 2008, p. 5291-5299, Vol. 190, No. 15
0021-9193/08/$08.00+0     doi:10.1128/JB.00288-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Global Regulation by (p)ppGpp and CodY in Streptococcus mutans{triangledown} ,{dagger}

José A. Lemos,1* Marcelle M. Nascimento,2 Vanessa K. Lin,2 Jacqueline Abranches,1 and Robert A. Burne2

Department of Microbiology and Immunology and Center for Oral Biology, University of Rochester Medical Center, Rochester, New York 14642,1 Department of Oral Biology, University of Florida College of Dentistry, Gainesville, Florida 326102

Received 26 February 2008/ Accepted 16 May 2008

The RelA, RelP, and RelQ enzymes are responsible for the production of the alarmone (p)ppGpp in Streptococcus mutans. A strain lacking all three synthetases ({Delta}relAPQ) does not grow in minimal medium lacking the branched-chain amino acids (BCAA) leucine or valine but grows well if isoleucine is also omitted. Here, we investigated whether there was a correlation between growth in the absence of leucine and valine with (p)ppGpp pools and the activation of CodY. By using a combination of single, double, and triple mutants lacking the (p)ppGpp synthetase enzymes, we demonstrated that the ability to grow in the absence of leucine or valine required basal levels of (p)ppGpp production by RelP and RelQ. The introduction of a codY mutation into the {Delta}relAPQ strain fully restored growth in medium lacking leucine or valine, revealing that the growth-defective phenotype of {Delta}relAPQ was directly linked to CodY. Lowering GTP levels through the addition of decoyinine did not alleviate CodY repression or affect the expression of genes involved in BCAA biosynthesis, suggesting that S. mutans CodY is not activated by GTP. The results of phenotypic studies revealed that the codY mutant had a reduced capacity to form biofilms and that its growth was more sensitive to low pH, showing a role for CodY in two key virulence properties of S. mutans. Microarray results revealed the extent of the CodY regulon. Notably, the identification of putative CodY-binding boxes upstream of genes that were downregulated in the codY mutant indicates that CodY may also function as a transcriptional activator in S. mutans.

* Corresponding author. Mailing address: Center for Oral Biology, Box 611, 601 Elmwood Ave., University of Rochester Medical Center, Rochester, NY 14642. Phone: (585) 275-1850. Fax: (585) 276-0190. E-mail: jose_lemos{at}urmc.rochester.edu

{triangledown} Published ahead of print on 6 June 2008.

{dagger} Supplemental material for this article may be found at http://jb.asm.org/.

Journal of Bacteriology, August 2008, p. 5291-5299, Vol. 190, No. 15
0021-9193/08/$08.00+0     doi:10.1128/JB.00288-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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