Toxin secretion and trafficking by Mycobacterium tuberculosis

David Pajuelo, Uday Tak, Lei Zhang, Olga Danilchanka, Anna D. Tischler and Michael Niederweis ()
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David Pajuelo: University of Alabama at Birmingham
Uday Tak: University of Alabama at Birmingham
Lei Zhang: University of Alabama at Birmingham
Olga Danilchanka: University of Alabama at Birmingham
Anna D. Tischler: University of Minnesota Twin Cities
Michael Niederweis: University of Alabama at Birmingham

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-26925-1

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