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An NAD+ Phosphorylase Toxin Triggers Mycobacterium tuberculosis Cell Death

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An NAD+ Phosphorylase Toxin Triggers Mycobacterium tuberculosis Cell Death. / Freire, Diana Mendes; Gutierrez, Claude; Garza-Garcia, Acely; Grabowska, Anna D; Sala, Ambre J; Ariyachaokun, Kanchiyaphat; Panikova, Terezie; Beckham, Katherine S H; Colom, André; Pogenberg, Vivian; Cianci, Michele; Tuukkanen, Anne; Boudehen, Yves-Marie; Peixoto, Antonio; Botella, Laure; Svergun, Dmitri I; Schnappinger, Dirk; Schneider, Thomas R; Genevaux, Pierre; de Carvalho, Luiz Pedro Sorio; Wilmanns, Matthias; Parret, Annabel H A; Neyrolles, Olivier.

In: MOL CELL, Vol. 73, No. 6, 21.03.2019, p. 1282-1291.e8.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Freire, DM, 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, LPS, Wilmanns, M, Parret, AHA & Neyrolles, O 2019, 'An NAD+ Phosphorylase Toxin Triggers Mycobacterium tuberculosis Cell Death', MOL CELL, vol. 73, no. 6, pp. 1282-1291.e8. https://doi.org/10.1016/j.molcel.2019.01.028

APA

Freire, D. M., Gutierrez, C., Garza-Garcia, A., Grabowska, A. D., Sala, A. J., Ariyachaokun, K., Panikova, T., Beckham, K. S. H., Colom, A., Pogenberg, V., Cianci, M., Tuukkanen, A., Boudehen, Y-M., Peixoto, A., Botella, L., Svergun, D. I., Schnappinger, D., Schneider, T. R., Genevaux, P., ... Neyrolles, O. (2019). An NAD+ Phosphorylase Toxin Triggers Mycobacterium tuberculosis Cell Death. MOL CELL, 73(6), 1282-1291.e8. https://doi.org/10.1016/j.molcel.2019.01.028

Vancouver

Freire DM, Gutierrez C, Garza-Garcia A, Grabowska AD, Sala AJ, Ariyachaokun K et al. An NAD+ Phosphorylase Toxin Triggers Mycobacterium tuberculosis Cell Death. MOL CELL. 2019 Mar 21;73(6):1282-1291.e8. https://doi.org/10.1016/j.molcel.2019.01.028

Bibtex

@article{cfec98030c734d50b038caa01b418275,
title = "An NAD+ Phosphorylase Toxin Triggers Mycobacterium tuberculosis Cell Death",
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 {\AA}-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.",
author = "Freire, {Diana Mendes} and Claude Gutierrez and Acely Garza-Garcia and Grabowska, {Anna D} and Sala, {Ambre J} and Kanchiyaphat Ariyachaokun and Terezie Panikova and Beckham, {Katherine S H} and Andr{\'e} Colom and Vivian Pogenberg and Michele Cianci and Anne Tuukkanen and Yves-Marie Boudehen and Antonio Peixoto and Laure Botella and Svergun, {Dmitri I} and Dirk Schnappinger and Schneider, {Thomas R} and Pierre Genevaux and {de Carvalho}, {Luiz Pedro Sorio} and Matthias Wilmanns and Parret, {Annabel H A} and Olivier Neyrolles",
note = "Crown Copyright {\textcopyright} 2019. Published by Elsevier Inc. All rights reserved.",
year = "2019",
month = mar,
day = "21",
doi = "10.1016/j.molcel.2019.01.028",
language = "English",
volume = "73",
pages = "1282--1291.e8",
journal = "MOL CELL",
issn = "1097-2765",
publisher = "Cell Press",
number = "6",

}

RIS

TY - JOUR

T1 - An NAD+ Phosphorylase Toxin Triggers Mycobacterium tuberculosis Cell Death

AU - Freire, Diana Mendes

AU - Gutierrez, Claude

AU - Garza-Garcia, Acely

AU - Grabowska, Anna D

AU - Sala, Ambre J

AU - Ariyachaokun, Kanchiyaphat

AU - Panikova, Terezie

AU - Beckham, Katherine S H

AU - Colom, André

AU - Pogenberg, Vivian

AU - Cianci, Michele

AU - Tuukkanen, Anne

AU - Boudehen, Yves-Marie

AU - Peixoto, Antonio

AU - Botella, Laure

AU - Svergun, Dmitri I

AU - Schnappinger, Dirk

AU - Schneider, Thomas R

AU - Genevaux, Pierre

AU - de Carvalho, Luiz Pedro Sorio

AU - Wilmanns, Matthias

AU - Parret, Annabel H A

AU - Neyrolles, Olivier

N1 - Crown Copyright © 2019. Published by Elsevier Inc. All rights reserved.

PY - 2019/3/21

Y1 - 2019/3/21

N2 - 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.

AB - 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.

U2 - 10.1016/j.molcel.2019.01.028

DO - 10.1016/j.molcel.2019.01.028

M3 - SCORING: Journal article

C2 - 30792174

VL - 73

SP - 1282-1291.e8

JO - MOL CELL

JF - MOL CELL

SN - 1097-2765

IS - 6

ER -