Model of CNF_Y toxin function.

<p>Adhesin-mediated interaction of <i>Y. pseudotuberculosis</i> with macrophages induces activation of RhoA which induces T3SS-promoted Yop delivery into the phagocyte. Yop translocation leads to blockage of phagocytosis and YopJ-mediated apoptotic cell death. In CNF_Y-producing <i>Y. pseudotuberculosis</i>, prior or parallel to the interaction of the bacteria with phagocytes, the CNF_Y toxin is secreted via outer membrane vesicles. Most likely CNF_Y-containing vesicles are internalized through receptor-mediated endocytosis, transferred via early endosomes (EE) to acidic compartments (late endosomes, LE) where the toxin is translocated across the bilayer into the cytosol by a low pH-dependent mechanism. Liberation of CNF_Y leads to activation of small Rho GTPases, in particular RhoA, and this amplifies Yop delivery and cell death. Rho GTPase activation was shown to promote pore formation of the T3SS, which appear to activate caspase-1 <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003746#ppat.1003746-Mejia1" target="_blank">[26]</a>, <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003746#ppat.1003746-Brodsky1" target="_blank">[74]</a>. Furthermore, enhanced cell death can lead to an accelerated proinflammatory immune response known to raise the level of activated macrophages in which <i>Yersinia</i> triggers activation of caspase-1 <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003746#ppat.1003746-Bergsbaken1" target="_blank">[66]</a>. Induction of caspase-1 leads to secretion of inflammatory cytokines and triggers cell death by inflammatory pyroptosis. In parallel, uncontrolled proliferation of the bacteria will lead to higher toxin concentrations, which will further enhance activation of Rac1, Cdc42 and RhoA and potentiate inflammatory pyroptosis.