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<p>Bacterial pathogens must withstand metal-induced stress during infection, yet the mechanisms by which they sense and respond to toxic metal ions remain incompletely understood. Here, we uncover a previously unrecognized mechanism in <i>Mycobacterium tuberculosis</i>, the causative agent of tuberculosis, which assembles dynamic, membrane-associated platforms organized by PacL proteins to mediate resistance to multiple metals. The small membrane-associated proteins PacL1, PacL2, and PacL3 coordinate the clustering of P-type ATPase pumps, namely CtpC, CtpG, and CtpV, into functional complexes that we term <i>effluxosomes</i>. Using single-particle tracking, we reveal distinct dynamic populations, with highly mobile PacL proteins integrating into more slowly mobile effluxosomes. PacL proteins stabilize CtpC and CtpG within these assemblies, promoting cross-resistance to zinc and cadmium, with PacL1 acting as a multi-substrate metallochaperone that binds zinc, cadmium, and copper <i>via</i> a conserved C-terminal motif. Single-molecule-based super-resolution microscopy shows that conserved residues within the PacL transmembrane domain are essential for effluxosome assembly. Strikingly, proximity labeling reveals a broad PacL1 interaction network, suggesting that effluxosomes contribute to a wider stress adaptation program. These findings establish effluxosomes as dynamic membrane machineries that orchestrate coordinated multi-metal resistance in <i>M. tuberculosis</i>, opening new avenues for antimicrobial targeting.</p>

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Membrane-associated effluxosomes coordinate multi-metal resistance in Mycobacterium tuberculosis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月13日

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  • Pierre Dupuy,
  • Yves-Marie Boudehen,
  • Marion Faucher,
  • John A Buglino,
  • Allison Fay,
  • Sylvain Cantaloube,
  • Yasmina Grimoire,
  • Julien Marcoux,
  • Florian Levet,
  • Laetitia Bettarel,
  • Bertille Voisin,
  • Jérôme Rech,
  • Jean-Yves Bouet,
  • Olivier Saurel,
  • Jean-Baptiste Sibarita,
  • Michael Glickman,
  • Claude Gutierrez,
  • Olivier Neyrolles

摘要

Bacterial pathogens must withstand metal-induced stress during infection, yet the mechanisms by which they sense and respond to toxic metal ions remain incompletely understood. Here, we uncover a previously unrecognized mechanism in Mycobacterium tuberculosis, the causative agent of tuberculosis, which assembles dynamic, membrane-associated platforms organized by PacL proteins to mediate resistance to multiple metals. The small membrane-associated proteins PacL1, PacL2, and PacL3 coordinate the clustering of P-type ATPase pumps, namely CtpC, CtpG, and CtpV, into functional complexes that we term effluxosomes. Using single-particle tracking, we reveal distinct dynamic populations, with highly mobile PacL proteins integrating into more slowly mobile effluxosomes. PacL proteins stabilize CtpC and CtpG within these assemblies, promoting cross-resistance to zinc and cadmium, with PacL1 acting as a multi-substrate metallochaperone that binds zinc, cadmium, and copper via a conserved C-terminal motif. Single-molecule-based super-resolution microscopy shows that conserved residues within the PacL transmembrane domain are essential for effluxosome assembly. Strikingly, proximity labeling reveals a broad PacL1 interaction network, suggesting that effluxosomes contribute to a wider stress adaptation program. These findings establish effluxosomes as dynamic membrane machineries that orchestrate coordinated multi-metal resistance in M. tuberculosis, opening new avenues for antimicrobial targeting.