Mycobacterial resistance to zinc poisoning requires assembly of P-ATPase-containing membrane metal efflux platforms

Yves-Marie Boudehen, Marion Faucher, Xavier Maréchal, Roger Miras, Jérôme Rech, Yoann Rombouts, Olivier Sénèque, Maximilian Wallat, Pascal Demange, Jean-Yves Bouet, Olivier Saurel, Patrice Catty, Claude Gutierrez and Olivier Neyrolles ()
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Yves-Marie Boudehen: Université de Toulouse, CNRS, UPS
Marion Faucher: Université de Toulouse, CNRS, UPS
Xavier Maréchal: University Grenoble Alpes, CNRS, CEA, IRIG, Laboratoire de Chimie et Biologie des Métaux
Roger Miras: University Grenoble Alpes, CNRS, CEA, IRIG, Laboratoire de Chimie et Biologie des Métaux
Jérôme Rech: Université de Toulouse, UPS
Yoann Rombouts: Université de Toulouse, CNRS, UPS
Olivier Sénèque: University Grenoble Alpes, CNRS, CEA, IRIG, Laboratoire de Chimie et Biologie des Métaux
Maximilian Wallat: Université de Toulouse, CNRS, UPS
Pascal Demange: Université de Toulouse, CNRS, UPS
Jean-Yves Bouet: Université de Toulouse, UPS
Olivier Saurel: Université de Toulouse, CNRS, UPS
Patrice Catty: University Grenoble Alpes, CNRS, CEA, IRIG, Laboratoire de Chimie et Biologie des Métaux
Claude Gutierrez: Université de Toulouse, CNRS, UPS
Olivier Neyrolles: Université de Toulouse, CNRS, UPS

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract The human pathogen Mycobacterium tuberculosis requires a P1B-ATPase metal exporter, CtpC (Rv3270), for resistance to zinc poisoning. Here, we show that zinc resistance also depends on a chaperone-like protein, PacL1 (Rv3269). PacL1 contains a transmembrane domain, a cytoplasmic region with glutamine/alanine repeats and a C-terminal metal-binding motif (MBM). PacL1 binds Zn2+, but the MBM is required only at high zinc concentrations. PacL1 co-localizes with CtpC in dynamic foci in the mycobacterial plasma membrane, and the two proteins form high molecular weight complexes. Foci formation does not require flotillin nor the PacL1 MBM. However, deletion of the PacL1 Glu/Ala repeats leads to loss of CtpC and sensitivity to zinc. Genes pacL1 and ctpC appear to be in the same operon, and homologous gene pairs are found in the genomes of other bacteria. Furthermore, PacL1 colocalizes and functions redundantly with other PacL orthologs in M. tuberculosis. Overall, our results indicate that PacL proteins may act as scaffolds that assemble P-ATPase-containing metal efflux platforms mediating bacterial resistance to metal poisoning.

Date: 2022
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DOI: 10.1038/s41467-022-32085-7

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