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

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Abstract
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 abundant Mycobacterium 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 tRNA Cys 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.
Funding Information
  • Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (99999.013433/2013-00)
  • New Jersey Commission on Cancer Research (DFHS18PPC045)
  • HHS | National Institutes of Health (AI135461)
  • HHS | National Institutes of Health (AI154464)

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