Ponente
Descripción
Sticholysin II (StII) is a 20 kDa pore-forming protein (PFP) with high cytolytic activity produced by a sea anemone. Binding to cell membranes lead to the formation of 2 nm diameter pores eventually leading to cell death. Cell death is induced by nM concentrations of the protein and is characterized by the increase in cell volume and the release of intracellular contents to the extracellular medium, typical features of a necrotic cell death. Contrary to the current understanding of the mechanism of action of these PFPs, we demonstrated that subnanomolar concentrations of StII induce the activation of several intracellular pathways. Studies with specific inhibitors showed that kinases ERK1/2, RIP1 and CaMKII, are involved in the cell death mechanism induced by StII in several tumor cells. In addition, the toxin induced eIF2α phosphorylation and the extracellular release of HMGB1 protein. Calcium seems to have a prominent role in this landscape. The presence of calcium in the extracellular medium increases the cell death rate induced by StII, but even in the absence of Ca2+, StII elicits an increase in cytosolic Ca2+ derived from the endoplasmic reticulum. This Ca2+ is eventually captured by mitochondria evoking their fragmentation and other morphological changes. In brief, StII induces a regulated necrosis with the activation of several intracellular pathways.
