Characterization of a chromosomal toxin–antitoxin, Rv1102c–Rv1103c system in Mycobacterium tuberculosis

Toxin–antitoxin systems, ubiquitous in prokaryotic genomes, have been proposed to play an important role in several stress responses. While Mycobacterium tuberculosis contains more than 80 putative TA loci, the roles they play in this pathogen are yet to be studied. Here, we characterize a chromosomal Rv1102c–Rv1103c TA system in M. tuberculosis. We found that the Rv1102c toxin interacts with the Rv1103c antitoxin in a pull-down assay and the yeast two-hybrid system. Rv1102c cleaved the era mRNA in Escherichia coli, and cleavage was inhibited by co-expression of Rv1103c. Heterologous expression of Rv1102c led to growth arrest in E. coli, which was fully recovered only when Rv1103c was co-expressed in cis with Rv1102c, suggesting that the production and assembly of Rv1102c and Rv1103c are tightly linked. Our additional results indicate that translational coupling of the Rv1102c and Rv1103c genes is important for Rv1102c–Rv1103c binding. Finally, we discovered that the expression of Rv1102c induced growth arrest and increased the level of persister cells in Mycobacterium smegmatis. These results suggest that the Rv1102c–Rv1103c TA system could play a role in M. tuberculosis pathogenesis via generating bacilli that survive in the face of multidrug therapy.

Research highlights
► The Rv1102c toxin strongly interacts with the cognate Rv1103c antitoxin.
► Rv1102c, via the mRNA interferase activity, caused growth arrest in E. coli and M. smegmatis, which was fully alleviated by co-expression of Rv1103c in a translationally coupled manner.
► The expression of Rv1102c increases persistence in M. smegmatis, implying that Rv1102–Rv1103c TA system holds potential as new anti-tubercular targets.