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


Identification: Barth-Valdir


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Mycobacterium tuberculosis VapC4 toxin engages small ORFs to
initiate an integrated oxidative and copper stress response
Valdir C. Barth (1), Unnati Chauhan (1), Jumei Zeng (2), Robert N. Husson (2), and Nancy A. Woychik (1,3)

1 Department of Biochemistry and Molecular Biology, Rutgers University, Robert Wood Johnson Medical School, Piscataway, NJ 08854; 2 Division of Infectious Diseases, Department of Pediatrics, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115; 3 Member, Rutgers Cancer Institute of New Jersey

Among the 50 VapBC toxin-antitoxin (TA) systems in Mycobacterium tuberculosis (Mtb), VapBC4 is one of only three that are known to be essential for virulence because it is required for the establishment of Mtb infection in animal models. Yet, the molecular mechanism underlying the virulence of VapBC4, or any other class of Mtb TA system, is not known. We determined the molecular mechanism that underlies the essential role of VapC4 toxin in Mycobacterium tuberculosis (Mtb) virulence. VapC4 exclusively cleaves and inactivates tRNA-Cys leading to ribosome stalling at Cys codons within actively translating mRNAs. Cys-stalled ribosomes unexpectedly uncovered hundreds of unannotated Cys-codon containing genes. A subset of these unannotated genes comprises small Cys-rich ORFs that appear to function as Cys-responsive attenuators that control translation of downstream genes through ribosome stalling at tracts of Cys codons. Cys-attenuation at sORFs leads to slow growth and globally redirects metabolism toward the synthesis of mycothiol—the glutathione counterpart in this pathogen responsible for maintaining cellular redox homeostasis during oxidative stress—as well as into other related cellular pathways that defend against oxidative and copper stresses that would otherwise collaborate to eradicate Mtb within macrophages. Our ability to pinpoint activation or downregulation of pathways that collectively align with the hallmark phenotypes of Mtb in the nonreplicating persistent state brings to light a novel, direct and vital role for the VapC4 toxin in mediating these critical pathways that are essential for virulence.

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