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

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 Mycobacterium tuberculosis pathophysiology. We show that VapC36 interacts with cognate and noncognate antitoxins. We demonstrate that serX is degraded in vitro by VapC36. We show that VapC36 binds copper, which enhances its ribonuclease activity. Furthermore, we report that deletion of vapBC36 or vapC36 enhances the susceptibility of M. tuberculosis upon exposure to copper in vitro. Compared to the wild-type strain, ΔBC36 was attenuated for growth in guinea pigs. However, deletion of either vapC36 or vapBC36 did not affect M. tuberculosis growth in mice. Compared to the wild-type strain, the in vivo susceptibility of ΔC36 and ΔBC36 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.