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Journal of Bacteriology, March 2009, p. 1618-1630, Vol. 191, No. 5
0021-9193/09/$08.00+0     doi:10.1128/JB.01318-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Three Mycobacterium tuberculosis Rel Toxin-Antitoxin Modules Inhibit Mycobacterial Growth and Are Expressed in Infected Human Macrophages{triangledown}

Shaleen B. Korch,1* Heidi Contreras,1 and Josephine E. Clark-Curtiss1,2

Center for Infectious Diseases and Vaccinology, Biodesign Institute,1 School of Life Sciences, Arizona State University, Tempe, Arizona 852872

Received 18 September 2008/ Accepted 19 December 2008

Mycobacterium tuberculosis protein pairs Rv1246c-Rv1247c, Rv2865-Rv2866, and Rv3357-Rv3358, here named RelBE, RelFG, and RelJK, respectively, were identified based on homology to the Escherichia coli RelBE toxin:antitoxin (TA) module. In this study, we have characterized each Rel protein pair and have established that they are functional TA modules. Overexpression of individual M. tuberculosis rel toxin genes relE, relG, and relK induced growth arrest in Mycobacterium smegmatis; a phenotype that was completely reversible by expression of their cognate antitoxin genes, relB, relF, and relJ, respectively. We also provide evidence that RelB and RelE interact directly, both in vitro and in vivo. Analysis of the genetic organization and regulation established that relBE, relFG, and relJK form bicistronic operons that are cotranscribed and autoregulated, in a manner unlike typical TA modules. RelB and RelF act as transcriptional activators, inducing expression of their respective promoters. However, RelBE, RelFG, and RelJK (together) repress expression to basal levels of activity, while RelJ represses promoter activity altogether. Finally, we have determined that all six rel genes are expressed in broth-grown M. tuberculosis, whereas relE, relF, and relK are expressed during infection of human macrophages. This is the first demonstration of M. tuberculosis expressing TA modules in broth culture and during infection of human macrophages.

* Corresponding author. Mailing address: Center for Infectious Diseases and Vaccinology, Biodesign Institute, Arizona State University, 1001 S. McAllister Avenue, Tempe, AZ 85287. Phone: (480) 727-0490. Fax: (480) 727-0466. E-mail: Shaleen.Korch{at}asu.edu

{triangledown} Published ahead of print on 29 December 2008.

Journal of Bacteriology, March 2009, p. 1618-1630, Vol. 191, No. 5
0021-9193/09/$08.00+0     doi:10.1128/JB.01318-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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