Fig. 7. Model of EsxE-EsxF mediated toxin secretion by Mtb.

During intracellular infection of macrophages Mtb produces the outer membrane protein CpnT, which enables nutrient uptake and whose secreted C-terminal TNT domain is the major toxin of Mtb. TNT is only toxic when it gains access to the macrophage cytosol after rupture of the phagosomal membrane. EsxE-EsxF heterodimers form large, oligomeric complexes, which bind to membranes and form membrane-spanning pores, which extend to the cell surface. This process is required for export of CpnT to the cell surface of Mtb. EsxEF and CpnT/TNT are then co-secreted and released into the macrophage cytosol leading to cell death. In the absence of EsxEF, CpnT is mislocalized and is possibly degraded in the cytosol of Mtb to prevent self-intoxication. This figure was created using Biorender.