Figure 6. Model of the functional ESX-1 secretion apparatus and the effect of the modified eccCa1 (Rv3870) in M.tb DK9897.

(a) The core structure of the ESX-1 system is formed by the conserved components EccB1, EccCa1, EccCb1, EccD1 and EccE1, each possessing transmembrane region(s) spanning the mycobacterial plasma membrane⁶⁴. The EccC is an ATP-driven translocase consisting of two subunits, EccCa1 and EccCb1, which are assembled once EccCb1 binds its target substrate, in this case, the EsxA/EsxB heterodimer, where EccCb1 interacts with the carboxy-terminal signal sequence of EsxB (marked as C in the figure)⁶⁵,⁶⁶. EsxB functions as a chaperone for EsxA secretion, which is a major ESX-1 virulence factor²¹. The secretion of EsxA/EsxB is co-dependent with the secretion of EspC/EspA and the C-terminus of EspC targets for the interaction with the cytosolic ATPase EccA1⁶⁷,⁶⁸. EspC polymerizes during secretion, indicating that EccA1 and EspA might function as cytosolic chaperones⁶⁹. The polymerization of EspC results in the formation of a surface-exposed filamentous structure that spans the entire cell envelope⁶⁹, possibly serving as a channel responsible for transporting ESX-1 substrates. (b) The truncated EccCa1 of M.tb DK9897 is unable to bind the EccCb1/EsxA/EsxB complex and is thus unable to secrete the EsxA/EsxB heterodimer. The secretion of EsxA/EsxB and EspA/EspC are mutually co-dependent⁶⁷, meaning that the secretion of EspC is presumably also disrupted in M.tb DK9897.