ESX/Type VII Secretion Systems-An Important Way Out for Mycobacterial Proteins

Abstract

The causative agent of human tuberculosis, Mycobacterium tuberculosis, has a complex lipid-rich diderm envelope, which acts as a major barrier protecting the bacterium against the hostile environment inside the host cells. For the transfer of diverse molecules across this complex cell envelope, M. tuberculosis has a series of general and specialized protein secretion systems, characterized by the SecA general secretion pathway, the twin-arginine translocation pathway, and five specific ESX type VII secretion systems. In this review, we focus on the latter systems, known as ESX-1 to ESX-5, which were first discovered almost 20 years ago during the in silico analysis of the genome sequence of M. tuberculosis H37Rv. Since then, these systems have been the subject of highly dynamic research due to their involvement in several key biological processes and host-pathogen interactions of the tubercle bacilli.

FIGURE 1

Genetic organization of the ESX loci. Shown is a schematic representation of the approximative genomic sites of the ESX-1 to ESX-5 clusters in the M. tuberculosis H37Rv genome. Gene nomenclature and gene color scheme were adapted from reference .

FIGURE 2

Representation of top and side views of the ESX/T7S system based on recent structural data generated by cryo-electron microscopy and single-particle analysis on an ESX-5 system from Mycobacterium xenopi, in comparison to selected examples of secretion systems from Gram-negative bacteria. The positions of the inner membrane (IM), outer membrane (OM), and mycomembrane (MM) are indicated. Adapted from reference , with permission.

FIGURE 3

Interplay of ESX-1 and ESX-3 in host-pathogen interactions. ESX-1 is essential for the bacterial phagosome-to-cytosol transition by involving a cGAS/STING/TBK1/IRF-3/type I interferon signalling axis and AIM2 and NLRP3 inflammasome activities. In an ESX-1-dependent manner, the ESCRT machinery is recruited to phagosomes, while ESX-3 effectors (EsxG-EsxH) antagonize the host damage response by blocking the recruitment of HRS, ESCRT-III, and GAL3. The scheme is adapted from reference , with some additions from reference , with permission.