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MenT nucleotidyltransferase toxins extend tRNA acceptor stems and can be inhibited by asymmetrical antitoxin binding

Author

Listed:
  • Xibing Xu

    (Université de Toulouse, CNRS, Université Toulouse III - Paul Sabatier (UT3))

  • Ben Usher

    (Durham University, South Road)

  • Claude Gutierrez

    (Université de Toulouse, CNRS, Université Toulouse III - Paul Sabatier (UT3))

  • Roland Barriot

    (Université de Toulouse, CNRS, Université Toulouse III - Paul Sabatier (UT3))

  • Tom J. Arrowsmith

    (Durham University, South Road)

  • Xue Han

    (Université de Toulouse, CNRS, Université Toulouse III - Paul Sabatier (UT3))

  • Peter Redder

    (Université de Toulouse, CNRS, Université Toulouse III - Paul Sabatier (UT3))

  • Olivier Neyrolles

    (Université de Toulouse, CNRS, Université Toulouse III - Paul Sabatier (UT3))

  • Tim R. Blower

    (Durham University, South Road)

  • Pierre Genevaux

    (Université de Toulouse, CNRS, Université Toulouse III - Paul Sabatier (UT3))

Abstract

Mycobacterium tuberculosis, the bacterium responsible for human tuberculosis, has a genome encoding a remarkably high number of toxin-antitoxin systems of largely unknown function. We have recently shown that the M. tuberculosis genome encodes four of a widespread, MenAT family of nucleotidyltransferase toxin-antitoxin systems. In this study we characterize MenAT1, using tRNA sequencing to demonstrate MenT1 tRNA modification activity. MenT1 activity is blocked by MenA1, a short protein antitoxin unrelated to the MenA3 kinase. X-ray crystallographic analysis shows blockage of the conserved MenT fold by asymmetric binding of MenA1 across two MenT1 protomers, forming a heterotrimeric toxin-antitoxin complex. Finally, we also demonstrate tRNA modification by toxin MenT4, indicating conserved activity across the MenT family. Our study highlights variation in tRNA target preferences by MenT toxins, selective use of nucleotide substrates, and diverse modes of MenA antitoxin activity.

Suggested Citation

  • Xibing Xu & Ben Usher & Claude Gutierrez & Roland Barriot & Tom J. Arrowsmith & Xue Han & Peter Redder & Olivier Neyrolles & Tim R. Blower & Pierre Genevaux, 2023. "MenT nucleotidyltransferase toxins extend tRNA acceptor stems and can be inhibited by asymmetrical antitoxin binding," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40264-3
    DOI: 10.1038/s41467-023-40264-3
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    References listed on IDEAS

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    1. Hatice Akarsu & Patricia Bordes & Moise Mansour & Donna-Joe Bigot & Pierre Genevaux & Laurent Falquet, 2019. "TASmania: A bacterial Toxin-Antitoxin Systems database," PLOS Computational Biology, Public Library of Science, vol. 15(4), pages 1-28, April.
    2. Patricia Bordes & Ambre Julie Sala & Sara Ayala & Pauline Texier & Nawel Slama & Anne-Marie Cirinesi & Valérie Guillet & Lionel Mourey & Pierre Genevaux, 2016. "Chaperone addiction of toxin–antitoxin systems," Nature Communications, Nature, vol. 7(1), pages 1-12, December.
    3. Prabhakar Tiwari & Garima Arora & Mamta Singh & Saqib Kidwai & Om Prakash Narayan & Ramandeep Singh, 2015. "MazF ribonucleases promote Mycobacterium tuberculosis drug tolerance and virulence in guinea pigs," Nature Communications, Nature, vol. 6(1), pages 1-13, May.
    4. Moise Mansour & Emmanuel Giudice & Xibing Xu & Hatice Akarsu & Patricia Bordes & Valérie Guillet & Donna-Joe Bigot & Nawel Slama & Gaetano D’urso & Sophie Chat & Peter Redder & Laurent Falquet & Lione, 2022. "Substrate recognition and cryo-EM structure of the ribosome-bound TAC toxin of Mycobacterium tuberculosis," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    5. Prabhakar Tiwari & Garima Arora & Mamta Singh & Saqib Kidwai & Om Prakash Narayan & Ramandeep Singh, 2015. "Correction: Corrigendum: MazF ribonucleases promote Mycobacterium tuberculosis drug tolerance and virulence in guinea pigs," Nature Communications, Nature, vol. 6(1), pages 1-1, November.
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    Cited by:

    1. Tom J. Arrowsmith & Xibing Xu & Shangze Xu & Ben Usher & Peter Stokes & Megan Guest & Agnieszka K. Bronowska & Pierre Genevaux & Tim R. Blower, 2024. "Inducible auto-phosphorylation regulates a widespread family of nucleotidyltransferase toxins," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    2. Tannu Priya Gosain & Saurabh Chugh & Zaigham Abbas Rizvi & Neeraj Kumar Chauhan & Saqib Kidwai & Krishan Gopal Thakur & Amit Awasthi & Ramandeep Singh, 2024. "Mycobacterium tuberculosis strain with deletions in menT3 and menT4 is attenuated and confers protection in mice and guinea pigs," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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