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

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, Lionel Mourey, Reynald Gillet () and Pierre Genevaux ()
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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
Patricia Bordes: Université de Toulouse, CNRS, UPS
Valérie Guillet: Université de Toulouse, CNRS, UPS
Donna-Joe Bigot: 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

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-30373-w

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