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Title: VapC toxins from Mycobacterium tuberculosis are ribonucleases that differentially inhibit growth and are neutralized by cognate vapB antitoxins
Authors: Ahidjo B.A. 
Kuhnert D.
McKenzie J.L.
Machowski E.E.
Gordhan B.G.
Arcus V.
Abrahams G.L.
Mizrahi V.
Keywords: antitoxin
bacterial toxin
unclassified drug
vapB toxin
vapC toxin
bacterial protein
bacterial gene
bacterial growth
controlled study
enzyme activity
gene deletion
gene expression regulation
gene function
gene locus
gene overexpression
genetic selection
growth inhibition
Mycobacterium smegmatis
Mycobacterium tuberculosis
promoter region
protein expression
protein function
protein protein interaction
toxin analysis
growth, development and aging
Mycobacterium tuberculosis
Mycobacterium tuberculosis
Bacterial Proteins
Gene Expression Regulation, Bacterial
Mycobacterium tuberculosis
Issue Date: 2011
Publisher: Public Library of Science
Citation: Ahidjo B.A., Kuhnert D., McKenzie J.L., Machowski E.E., Gordhan B.G., Arcus V., Abrahams G.L., Mizrahi V. (2011). VapC toxins from Mycobacterium tuberculosis are ribonucleases that differentially inhibit growth and are neutralized by cognate vapB antitoxins. PLoS ONE 6 (6) : e21738. ScholarBank@NUS Repository.
Abstract: The chromosome of Mycobacterium tuberculosis (Mtb) encodes forty seven toxin-antitoxin modules belonging to the VapBC family. The role of these modules in the physiology of Mtb and the function(s) served by their expansion are unknown. We investigated ten vapBC modules from Mtb and the single vapBC from M. smegmatis. Of the Mtb vapCs assessed, only Rv0549c, Rv0595c, Rv2549c and Rv2829c were toxic when expressed from a tetracycline-regulated promoter in M. smegmatis. The same genes displayed toxicity when conditionally expressed in Mtb. Toxicity of Rv2549c in M. smegmatis correlated with the level of protein expressed, suggesting that the VapC level must exceed a threshold for toxicity to be observed. In addition, the level of Rv2456 protein induced in M. smegmatis was markedly lower than Rv2549c, which may account for the lack of toxicity of this and other VapCs scored as 'non-toxic'. The growth inhibitory effects of toxic VapCs were neutralized by expression of the cognate VapB as part of a vapBC operon or from a different chromosomal locus, while that of non-cognate antitoxins did not. These results demonstrated a specificity of interaction between VapCs and their cognate VapBs, a finding corroborated by yeast two-hybrid analyses. Deletion of selected vapC or vapBC genes did not affect mycobacterial growth in vitro, but rendered the organisms more susceptible to growth inhibition following toxic VapC expression. However, toxicity of 'non-toxic' VapCs was not unveiled in deletion mutant strains, even when the mutation eliminated the corresponding cognate VapB, presumably due to insufficient levels of VapC protein. Together with the ribonuclease (RNase) activity demonstrated for Rv0065 and Rv0617 - VapC proteins with similarity to Rv0549c and Rv3320c, respectively - these results suggest that the VapBC family potentially provides an abundant source of RNase activity in Mtb, which may profoundly impact the physiology of the organism. © 2011 Ahidjo et al.
Source Title: PLoS ONE
ISSN: 19326203
DOI: 10.1371/journal.pone.0021738
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