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.
|Original language||English (US)|
|State||Published - Dec 2021|
Bibliographical noteFunding Information:
We thank Drs. JoAnn Tufariello and William Jacobs for providing the Mtb esx-3 deletion mutant, Dr. Moon Nahm for the generous permission to use his flow cytometer, Dr. Jim Sun for constructing the cpnT operon expression plasmid pML3042, and Dr. Avishek Mitra for testing the Mtb eccC2 and eccC4 deletion mutants for PDIM. DMN-Trehalose (DMN-Tre) was a kind gift from Drs. Mireille Kamariza, Samantha Grace Lyons Keyser, and Carolyn Bertozzi (Stanford University). This work was supported by the National Institutes of Health (NIH) grant AI121354 to M.N.
© 2021, The Author(s).