Mycobacterium tuberculosis VapC4 toxin engages small ORFs to initiate an integrated oxidative and copper stress response

Significance Toxin–antitoxin (TA) systems are proposed to protect bacteria from deadly stresses encountered in their environmental niches. Yet clear examples supporting this hypothesis are lacking. The abundantMycobacterium tuberculosis (Mtb) TA systems are implicated in enabling this pathogen to evade killing by our immune system and persist inside macrophages as a latent tuberculosis infection. We used a multiomics approach to track the activity of one TA system toxin, VapC4, and the series of molecular events it triggers. VapC4 first depletes tRNACys to mimic a state of Cys starvation. This reprograms Mtb metabolism to specifically defend against oxidative and copper stresses. Thus, VapC4 plays a direct and vital role in mediating these critical stress pathways essential for Mtb viability during infection.