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An NAD Phosphorylase Toxin Triggers Mycobacterium tuberculosis Cell Death.

TitleAn NAD Phosphorylase Toxin Triggers Mycobacterium tuberculosis Cell Death.
Publication TypeJournal Article
Year of Publication2019
AuthorsFreire DMendes, Gutierrez C, Garza-Garcia A, Grabowska AD, Sala AJ, Ariyachaokun K, Panikova T, Beckham KSH, Colom A, Pogenberg V, Cianci M, Tuukkanen A, Boudehen Y-M, Peixoto A, Botella L, Svergun DI, Schnappinger D, Schneider TR, Genevaux P, de Carvalho LPedro Sori, Wilmanns M, Parret AHA, Neyrolles O
JournalMol Cell
Volume73
Issue6
Pagination1282-1291.e8
Date Published2019 03 21
ISSN1097-4164
KeywordsAnimals, Antibiotics, Antitubercular, Antitoxins, Bacterial Load, Bacterial Proteins, Bacterial Toxins, Cells, Cultured, Disease Models, Animal, Female, Host-Pathogen Interactions, Humans, Kinetics, Macrophages, Mice, Inbred C57BL, Mice, SCID, Mice, Transgenic, Microbial Viability, Models, Molecular, Mycobacterium smegmatis, Mycobacterium tuberculosis, NAD, Phosphorylases, Protein Conformation, Toxin-Antitoxin Systems, Tuberculosis
Abstract

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.

DOI10.1016/j.molcel.2019.01.028
Alternate JournalMol Cell
PubMed ID30792174
PubMed Central IDPMC6436930
Grant List / / Wellcome Trust / United Kingdom
FC001060 / / Cancer Research UK / United Kingdom
FC001060 / / Medical Research Council / United Kingdom

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