Biochemical characterization of a chromosomal toxin–antitoxin system in <i>Mycobacterium tuberculosis</i>

Zhao, Longxuan; Zhang, Junjie

doi:10.1016/j.febslet.2008.01.045

Cited by 24 publications

(18 citation statements)

References 15 publications

(22 reference statements)

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“…In addition, there is a possibility that MazF toxin in complex with their cognate antitoxin can regulate transcription from their own promoter as reported in the case of MazEF6 (ref. 51). To establish a successful infection, Mtb must adapt to acidic, nitrosative, oxidative, nutrient-limiting and low-oxygen conditions encountered in the host.…”

Section: Discussionmentioning

confidence: 99%

MazF ribonucleases promote Mycobacterium tuberculosis drug tolerance and virulence in guinea pigs

et al. 2015

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Toxin-antitoxin (TA) systems are highly conserved in members of the Mycobacterium tuberculosis (Mtb) complex and have been proposed to play an important role in physiology and virulence. Nine of these TA systems belong to the mazEF family, encoding the intracellular MazF toxin and its antitoxin, MazE. By overexpressing each of the nine putative MazF homologues in Mycobacterium bovis BCG, here we show that Rv1102c (MazF3), Rv1991c (MazF6) and Rv2801c (MazF9) induce bacteriostasis. The construction of various single-, double-and triple-mutant Mtb strains reveals that these MazF ribonucleases contribute synergistically to the ability of Mtb to adapt to conditions such as oxidative stress, nutrient depletion and drug exposure. Moreover, guinea pigs infected with the triple-mutant strain exhibits significantly reduced bacterial loads and pathological damage in infected tissues in comparison with parental strain-infected guinea pigs. The present study highlights the importance of MazF ribonucleases in Mtb stress adaptation, drug tolerance and virulence.

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Section: Discussionmentioning

confidence: 99%

MazF ribonucleases promote Mycobacterium tuberculosis drug tolerance and virulence in guinea pigs

et al. 2015

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“…In addition, overexpression of MazF homologue Rv1991c inhibited the growth of M. smegmatis, which was moderately reversed after expression of its cognate antitoxin, Rv1991a (51). Mechanistically, M. tuberculosis MazF-mt3 and MazF-mt7 act as endoribonucleases, targeting the unique sequences CUĈ CU/UUĈ CU (MazF-mt3) and UĈ GCU (MazF-mt7) in single-stranded RNA (52).…”

Section: Discussionmentioning

confidence: 99%

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

Korch¹,

Contreras²,

2009

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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.

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“…In a separate study, 30 out of 38 putative TA systems from M. tuberculosis were functional when expressed in E. coli (61). Of the nine MazF homologs identified in M. tuberculosis, seven have been studied and shown to cause growth arrest when expressed in E. coli (49,62,63 (64,65). Further worked showed that expression of the RelE2 toxin in M. tuberculosis induced the formation of drug-specific persisters in vitro; however, deletion of relE2 did not affect the level of persisters of M. tuberculosis in rifampin-treated mice ruling out a role for relE2 in the generation of bacilli that survive multidrug therapy (66).…”

Section: Discussionmentioning

confidence: 99%

Toxin-Antitoxin Systems of Mycobacterium smegmatis Are Essential for Cell Survival

Frampton

Aggio

Villas‐Bôas

et al. 2012

Journal of Biological Chemistry

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Background: Mycobacteria harbor a vast array of toxin-antitoxin modules, but their roles remain largely unknown. Results: Deletion of all TA modules in Mycobacterium smegmatis caused a survival defect and alterations in amino acid metabolism. Conclusion:We demonstrate an essential role for TA modules in mycobacterial metabolism and survival. Significance: These results may explain the basis for 88 TA modules in M. tuberculosis where metabolism must be tightly controlled.

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Biochemical characterization of a chromosomal toxin–antitoxin system in Mycobacterium tuberculosis

Cited by 24 publications

References 15 publications

MazF ribonucleases promote Mycobacterium tuberculosis drug tolerance and virulence in guinea pigs

MazF ribonucleases promote Mycobacterium tuberculosis drug tolerance and virulence in guinea pigs

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

Toxin-Antitoxin Systems of Mycobacterium smegmatis Are Essential for Cell Survival

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