Crosstalk between the ancestral type VII secretion system ESX-4 and other T7SS in .

The type VII secretion system (T7SS) of secretes three substrate classes: Esx, Esp, and PE/PPE proteins, that play important roles in bacterial physiology and host interaction. Five subtypes of T7SS, namely ESX-1 to ESX-5, are present in . ESX-4 is the progenitor of T7SS but its function is not understood. We investigated the ESX-4 system in . We show that ESX-4 of does not secrete its cognate substrates, EsxT and EsxU, under the conditions tested. Paradoxically, the deletion of , an essential component of ESX-4, resulted in elevated secretion of protein substrates of ESX-1 and ESX-5. Consequently, the Δ mutant was more efficient in inducing actin cytoskeleton rearrangement, which led to enhanced phagocytosis by macrophages. Our results reveal an intimate crosstalk between the progenitor of T7SS and its more recent duplication and expansion, and provide new insight into the evolution of T7SS in mycobacteria.