An NAD+ phosphorylase toxin triggers Mycobacterium tuberculosis cell deathMore about Open Access at the Crick
Authors listDiana Mendes Freire Claude Gutierrez Acely Garza-Garcia Anna D Grabowska Ambre J Sala Kanchiyaphat Ariyachaokun Terezie Panikova Katherine SH Beckham André Colom Vivian Pogenberg Michele Cianci Anne Tuukkanen Yves-Marie Boudehen Antonio Peixoto Laure Botella Dmitri I Svergun Dirk Schnappinger Thomas R Schneider Pierre Genevaux Luiz Pedro Carvalho Matthias Wilmanns Annabel HA Parret Olivier Neyrolles
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.
Journal Molecular Cell
Issue number 6