Calcium Influx Rescues Adenylate Cyclase-Hemolysin from Rapid Cell Membrane Removal and Enables Phagocyte Permeabilization by Toxin Pores
Figure 13
Model of the calcium influx-triggered positive feedback mechanism of self-exacerbating potassium efflux due to protracted cell permeabilization by toxin pores.
Upon binding to the αMβ2 integrin (CD11b/CD18), the pore precursor conformers of dCyaA oligomerize within the bulk phase of target cell membrane and permeabilize cells for efflux of cytosolic potassium ions. In parallel, toxin translocation precursors insert into cellular membrane and conduct extracellular Ca2+ into cell cytosol. Elevation of [Ca2+]i in the submembrane compartment results in activation of talin cleavage by calpain and liberates the receptor with bound toxin translocation precursor within target membrane for lateral relocation into lipid rafts, where the translocation of the AC domain across plasma membrane is completed [15]. The entry of Ca2+ provokes deceleration of clathrin-dependent endocytic uptake of CyaA, thereby delaying removal of toxin pores from the cytoplasmic membrane. Protracted persistence of CyaA pores within cellular membrane then triggers a self-amplifying (positive) feedback loop mechanism that exacerbates cell permeabilization. The more potassium leaks out form cells, the more the clathrin-dependent endocytic removal of toxin pores from cellular membrane is decelerated and the more is the cell permeabilization and potassium leakage exacerbated. In contrast, the mutated dCyaA-KP and the CyaAΔAC hemolysin variants of CyaA are unable to conduct calcium ions into cells and are thus rapidly removed from the cytosolic membrane of cells by a membrane macropinocytosis mechanism that directs the mutant toxoids for rapid proteolytic degradation.