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Substrate recognition and cryo-EM structure of the ribosome-bound TAC toxin of Mycobacterium tuberculosis

Author

Listed:
  • Moise Mansour

    (Université de Toulouse, CNRS, UPS)

  • Emmanuel Giudice

    (Institut de Génétique et Développement de Rennes (IGDR), UMR6290, Université de Rennes, CNRS)

  • Xibing Xu

    (Université de Toulouse, CNRS, UPS)

  • Hatice Akarsu

    (University of Fribourg & Swiss Institute of Bioinformatics
    University of Bern)

  • Patricia Bordes

    (Université de Toulouse, CNRS, UPS)

  • Valérie Guillet

    (Université de Toulouse, CNRS, UPS)

  • Donna-Joe Bigot

    (Université de Toulouse, CNRS, UPS
    Université de Toulouse, CNRS, UPS)

  • Nawel Slama

    (Université de Toulouse, CNRS, UPS)

  • Gaetano D’urso

    (Institut de Génétique et Développement de Rennes (IGDR), UMR6290, Université de Rennes, CNRS)

  • Sophie Chat

    (Institut de Génétique et Développement de Rennes (IGDR), UMR6290, Université de Rennes, CNRS)

  • Peter Redder

    (Université de Toulouse, CNRS, UPS)

  • Laurent Falquet

    (University of Fribourg & Swiss Institute of Bioinformatics)

  • Lionel Mourey

    (Université de Toulouse, CNRS, UPS)

  • Reynald Gillet

    (Institut de Génétique et Développement de Rennes (IGDR), UMR6290, Université de Rennes, CNRS)

  • Pierre Genevaux

    (Université de Toulouse, CNRS, UPS)

Abstract

Toxins of toxin-antitoxin systems use diverse mechanisms to control bacterial growth. Here, we focus on the deleterious toxin of the atypical tripartite toxin-antitoxin-chaperone (TAC) system of Mycobacterium tuberculosis, whose inhibition requires the concerted action of the antitoxin and its dedicated SecB-like chaperone. We show that the TAC toxin is a bona fide ribonuclease and identify exact cleavage sites in mRNA targets on a transcriptome-wide scale in vivo. mRNA cleavage by the toxin occurs after the second nucleotide of the ribosomal A-site codon during translation, with a strong preference for CCA codons in vivo. Finally, we report the cryo-EM structure of the ribosome-bound TAC toxin in the presence of native M. tuberculosis cspA mRNA, revealing the specific mechanism by which the TAC toxin interacts with the ribosome and the tRNA in the P-site to cleave its mRNA target.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30373-w
    DOI: 10.1038/s41467-022-30373-w
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    References listed on IDEAS

    as
    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. Valérie Guillet & Patricia Bordes & Cécile Bon & Julien Marcoux & Virginie Gervais & Ambre Julie Sala & Suzana Dos Reis & Nawel Slama & Israel Mares-Mejía & Anne-Marie Cirinesi & Laurent Maveyraud & P, 2019. "Structural insights into chaperone addiction of toxin-antitoxin systems," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    4. 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.
    5. Sandip Kaledhonkar & Ziao Fu & Kelvin Caban & Wen Li & Bo Chen & Ming Sun & Ruben L. Gonzalez & Joachim Frank, 2019. "Late steps in bacterial translation initiation visualized using time-resolved cryo-EM," Nature, Nature, vol. 570(7761), pages 400-404, June.
    6. Valérie Guillet & Patricia Bordes & Cécile Bon & Julien Marcoux & Virginie Gervais & Ambre Julie Sala & Suzana Reis & Nawel Slama & Israel Mares-Mejía & Anne-Marie Cirinesi & Laurent Maveyraud & Pierr, 2019. "Publisher Correction: Structural insights into chaperone addiction of toxin-antitoxin systems," Nature Communications, Nature, vol. 10(1), pages 1-1, December.
    7. 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. Xibing Xu & Roland Barriot & Bertille Voisin & Tom J. Arrowsmith & Ben Usher & Claude Gutierrez & Xue Han & Carine Pagès & Peter Redder & Tim R. Blower & Olivier Neyrolles & Pierre Genevaux, 2024. "Nucleotidyltransferase toxin MenT extends aminoacyl acceptor ends of serine tRNAs to control Mycobacterium tuberculosis growth," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    2. 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.

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