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The  Mycobacterium tuberculosis  genome harbors an unusually high number of toxin-antitoxin (TA) systems. These TA systems have been implicated in establishing the nonreplicating persistent state of this pathogen during latent tuberculosis infection. More than half of the  M. tuberculosis  TA systems belong to the VapBC ( v irulence  a ssociated  p rotein) family. In this work, we first identified the RNA targets for the  M. tuberculosis  VapC-mt11 (VapC11, Rv1561) toxin  in vitro  to learn more about the general function of this family of toxins. Recombinant VapC-mt11 cleaved 15 of the 45  M. tuberculosis  tRNAs at a single site within their anticodon stem loop (ASL) to generate tRNA halves. Cleavage was dependent on the presence of a GG consensus sequence immediately before the cut site and a structurally intact ASL. However, in striking contrast to the broad enzyme activity exhibited  in vitro , we used a specialized RNA-seq method to demonstrate that tRNA cleavage was highly specific  in vivo . Expression of VapC-mt11 in  M. tuberculosis  resulted in cleavage of only two tRNA isoacceptors containing the GG consensus sequence, tRNA Gln32-CUG  and tRNA Leu3-CAG . Therefore, our results indicate that although  in vitro  studies are useful for identification of the class of RNA cleaved and consensus sequences required for accurate substrate recognition by endoribonuclease toxins, definitive RNA target identification requires toxin expression in their native host. The restricted  in vivo  specificity of VapC-mt11 suggests that it may be enlisted to surgically manipulate pathogen physiology in response to stress.

Accurate target identification for Mycobacterium tuberculosis endoribonuclease toxins requires expression in their native host