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A nucleotidyltransferase toxin inhibits growth of Mycobacterium tuberculosis through inactivation of tRNA acceptor stems

Cai, Y.; Usher, B.; Gutierrez, C.; Tolcan, A.; Mansour, M.; Fineran, P.C.; Condon, C.; Neyrolles, O.; Genevaux, P.; Blower, T.R.

A nucleotidyltransferase toxin inhibits growth of Mycobacterium tuberculosis through inactivation of tRNA acceptor stems Thumbnail


Authors

Y. Cai

B. Usher

C. Gutierrez

A. Tolcan

M. Mansour

P.C. Fineran

C. Condon

O. Neyrolles

P. Genevaux



Abstract

Toxin-antitoxin systems are widespread stress-responsive elements, many of whose functions remain largely unknown. Here, we characterize the four DUF1814-family nucleotidyltransferase-like toxins (MenT1–4) encoded by the human pathogen Mycobacterium tuberculosis. Toxin MenT3 inhibited growth of M. tuberculosis when not antagonized by its cognate antitoxin, MenA3. We solved the structures of toxins MenT3 and MenT4 to 1.6 and 1.2 Å resolution, respectively, and identified the biochemical activity and target of MenT3. MenT3 blocked in vitro protein expression and prevented tRNA charging in vivo. MenT3 added pyrimidines (C or U) to the 3′-CCA acceptor stems of uncharged tRNAs and exhibited strong substrate specificity in vitro, preferentially targeting tRNASer from among the 45 M. tuberculosis tRNAs. Our study identifies a previously unknown mechanism that expands the range of enzymatic activities used by bacterial toxins, uncovering a new way to block protein synthesis and potentially treat tuberculosis and other infections.

Citation

Cai, Y., Usher, B., Gutierrez, C., Tolcan, A., Mansour, M., Fineran, P., …Blower, T. (2020). A nucleotidyltransferase toxin inhibits growth of Mycobacterium tuberculosis through inactivation of tRNA acceptor stems. Science Advances, 6(31), Article eabb6651. https://doi.org/10.1126/sciadv.abb6651

Journal Article Type Article
Acceptance Date Jun 12, 2020
Online Publication Date Jul 29, 2020
Publication Date Jul 29, 2020
Deposit Date Jun 10, 2020
Publicly Available Date Jul 30, 2020
Journal Science Advances
Publisher American Association for the Advancement of Science
Peer Reviewed Peer Reviewed
Volume 6
Issue 31
Article Number eabb6651
DOI https://doi.org/10.1126/sciadv.abb6651

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http://creativecommons.org/licenses/by-nc/4.0/

Copyright Statement
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). https://creativecommons.org/licenses/by-nc/4.0/
This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.





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