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An NAD+ Phosphorylase Toxin Triggers Mycobacterium tuberculosis Cell Death

Diana Mendes Freire, Claude Gutierrez, Acely Garza-Garcia, Anna D. Grabowska, Ambre J. Sala, Kanchiyaphat Ariyachaokun, Terezie Panikova, Katherine S.H. Beckham, André Colom, Vivian Pogenberg, Michele Cianci, Anne Tuukkanen (+11 others)
2019 Molecular Cell  

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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
more » ... n. 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.
doi:10.1016/j.molcel.2019.01.028 pmid:30792174 pmcid:PMC6436930 fatcat:ziheklharjethjvexneepn3rti
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Diana Mendes Freire, Claude Gutierrez, Acely Garza-Garcia, Anna D. Grabowska, Ambre J. Sala, Kanchiyaphat Ariyachaokun, Terezie Panikova, Katherine S.H. 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 Sorio de Carvalho, Matthias Wilmanns, Annabel H.A. Parret, Olivier Neyrolles. "An NAD+ Phosphorylase Toxin Triggers Mycobacterium tuberculosis Cell Death." Molecular Cell 73.6 (2019) 1282-1291.e8