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Toxin secretion and trafficking by Mycobacterium tuberculosis

Author

Listed:
  • David Pajuelo

    (University of Alabama at Birmingham)

  • Uday Tak

    (University of Alabama at Birmingham
    University of Colorado Boulder, Jennie Smoly Caruthers Biotechnology Building B255)

  • Lei Zhang

    (University of Alabama at Birmingham)

  • Olga Danilchanka

    (University of Alabama at Birmingham
    Merck & Co., Inc.)

  • Anna D. Tischler

    (University of Minnesota Twin Cities)

  • Michael Niederweis

    (University of Alabama at Birmingham)

Abstract

The tuberculosis necrotizing toxin (TNT) is the major cytotoxicity factor of Mycobacterium tuberculosis (Mtb) in macrophages. TNT is the C-terminal domain of the outer membrane protein CpnT and gains access to the cytosol to kill macrophages infected with Mtb. However, molecular mechanisms of TNT secretion and trafficking are largely unknown. A comprehensive analysis of the five type VII secretion systems of Mtb revealed that the ESX-4 system is required for export of CpnT and surface accessibility of TNT. Furthermore, the ESX-2 and ESX-4 systems are required for permeabilization of the phagosomal membrane in addition to the ESX-1 system. Thus, these three ESX systems need to act in concert to enable trafficking of TNT into the cytosol of Mtb-infected macrophages. These discoveries establish new molecular roles for the two previously uncharacterized type VII secretion systems ESX-2 and ESX-4 and reveal an intricate link between toxin secretion and phagosomal permeabilization by Mtb.

Suggested Citation

  • David Pajuelo & Uday Tak & Lei Zhang & Olga Danilchanka & Anna D. Tischler & Michael Niederweis, 2021. "Toxin secretion and trafficking by Mycobacterium tuberculosis," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26925-1
    DOI: 10.1038/s41467-021-26925-1
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    References listed on IDEAS

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    1. Paolo S. Manzanillo & Janelle S. Ayres & Robert O. Watson & Angela C. Collins & Gianne Souza & Chris S. Rae & David S. Schneider & Ken Nakamura & Michael U. Shiloh & Jeffery S. Cox, 2013. "The ubiquitin ligase parkin mediates resistance to intracellular pathogens," Nature, Nature, vol. 501(7468), pages 512-516, September.
    2. Catalin M. Bunduc & Dirk Fahrenkamp & Jiri Wald & Roy Ummels & Wilbert Bitter & Edith N. G. Houben & Thomas C. Marlovits, 2021. "Structure and dynamics of a mycobacterial type VII secretion system," Nature, Nature, vol. 593(7859), pages 445-448, May.
    3. Uday Tak & Terje Dokland & Michael Niederweis, 2021. "Pore-forming Esx proteins mediate toxin secretion by Mycobacterium tuberculosis," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    4. Nikolaos Famelis & Angel Rivera-Calzada & Gianluca Degliesposti & Maria Wingender & Nicole Mietrach & J. Mark Skehel & Rafael Fernandez-Leiro & Bettina Böttcher & Andreas Schlosser & Oscar Llorca & Se, 2019. "Architecture of the mycobacterial type VII secretion system," Nature, Nature, vol. 576(7786), pages 321-325, December.
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