VapC36-mediated intrinsic stress adaption is required for copper tolerance and pathogenesis of <i>Mycobacterium tuberculosis</i>.

Abstract

Here, we have used a comprehensive, system-wide approach to delineate the function of the virulence-associated proteins B and C 36 (VapBC36) toxin-antitoxin (TA) system in <i>Mycobacterium tuberculosis</i> pathophysiology. We show that VapC36 interacts with cognate and noncognate antitoxins. We demonstrate that <i>serX</i> is degraded in vitro by VapC36. We show that VapC36 binds copper, which enhances its ribonuclease activity. Furthermore, we report that deletion of <i>vapBC36</i> or <i>vapC36</i> enhances the susceptibility of <i>M. tuberculosis</i> upon exposure to copper in vitro. Compared to the wild-type strain, Δ<i>BC36</i> was attenuated for growth in guinea pigs. However, deletion of either <i>vapC36</i> or <i>vapBC36</i> did not affect <i>M. tuberculosis</i> growth in mice. Compared to the wild-type strain, the in vivo susceptibility of Δ<i>C36 and</i> Δ<i>BC36</i> strains was increased in copper-fed mice. Together, these findings have enhanced our understanding of the regulation and contribution of TA systems in mycobacterial pathophysiology.