An NAD Phosphorylase Toxin Triggers Mycobacterium tuberculosis Cell Death.

Molecular cell, Volume: 73, Issue: 6
March 21, 2019
Diana Mendes Freire DM, Claude Gutierrez C, Acely Garza-Garcia A, Anna D Grabowska AD, Ambre J Sala AJ, Kanchiyaphat Ariyachaokun K, Terezie Panikova T, Katherine S H Beckham KSH, André Colom A, Vivian Pogenberg V, Michele Cianci M, Anne Tuukkanen A, Yves-Marie Boudehen YM, Antonio Peixoto A, Laure Botella L, Dmitri I Svergun DI, Dirk Schnappinger D, Thomas R Schneider TR, Pierre Genevaux P, Luiz Pedro Sorio de Carvalho LPS, Matthias Wilmanns M, Annabel H A Parret AHA, Olivier Neyrolles O

Toxin-antitoxin (TA) systems regulate fundamental cellular processes in bacteria and represent potential therapeutic targets. We report a new RES-Xre TA system in multiple human pathogens, including Mycobacterium tuberculosis. The toxin, MbcT, is bactericidal unless neutralized by its antitoxin MbcA. To investigate the mechanism, we solved the 1.8 Å-resolution crystal structure of the MbcTA complex. We found that MbcT resembles secreted NAD-dependent bacterial exotoxins, such as diphtheria toxin. Indeed, MbcT catalyzes NAD degradation in vitro and in vivo. Unexpectedly, the reaction is stimulated by inorganic phosphate, and our data reveal that MbcT is a NAD phosphorylase. In the absence of MbcA, MbcT triggers rapid M. tuberculosis cell death, which reduces mycobacterial survival in macrophages and prolongs the survival of infected mice. Our study expands the molecular activities employed by bacterial TA modules and uncovers a new class of enzymes that could be exploited to treat tuberculosis and other infectious diseases.

Courtesy of the U.S. National Library of Medicine