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Open Access Highly Accessed Research article

MazF6 toxin of Mycobacterium tuberculosis demonstrates antitoxin specificity and is coupled to regulation of cell growth by a Soj-like protein

Melissa V Ramirez1, Clinton C Dawson1, Rebecca Crew13, Kathleen England12 and Richard A Slayden1*

Author Affiliations

1 Mycobacteria Research Laboratories, Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO 80523, USA

2 Current address: Department of Infectious Diseases, Stanford University School of Medicine, Stanford, CA 94305, USA

3 Current address: Bacterial Diseases Branch, Division of Vector-Borne Diseases, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Fort Collins, CO USA

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BMC Microbiology 2013, 13:240  doi:10.1186/1471-2180-13-240

Published: 31 October 2013

Abstract

Background

Molecular programs employed by Mycobacterium tuberculosis (Mtb) for the establishment of non-replicating persistence (NRP) are poorly understood. In order to investigate mechanisms regulating entry into NRP, we asked how cell cycle regulation is linked to downstream adaptations that ultimately result in NRP. Based on previous reports and our recent studies, we reason that, in order to establish NRP, cells are halted in the cell cycle at the point of septum formation by coupled regulatory mechanisms.

Results

Using bioinformatic consensus modeling, we identified an alternative cell cycle regulatory element, SojMtb encoded by rv1708. SojMtb coordinates a regulatory mechanism involving cell cycle control at the point of septum formation and elicits the induction of the MazF6 toxin. MazF6 functions as an mRNA interferase leading to bacteriostasis that can be prevented by interaction with its cognate antitoxin, MazE6. Further, MazEF6 acts independently of other Maz family toxin:antitoxin pairs. Notably, sojMtb and mazEF6 transcripts where identified at 20, 40 and 100 days post-infection in increasing abundance indicating a role in adaption during chronic infection.

Conclusions

Here we present the first evidence of a coupled regulatory system in which cell cycle regulation via SojMtb is linked to downstream adaptations that are facilitated through the activity of the MazEF6 TA pair.

Keywords:
Mycobacterium tuberculosis; Cell cycle; MazF; Toxin:antitoxin; SojMtb