Using More Than 1 (Path)Way to Kill a Host Cell: Lessons From Enterotoxin.

enterotoxin (CPE) is responsible for the symptoms of common intestinal infections due to type F isolates. CPE is a pore-forming toxin that uses certain claudins as a receptor. Previous studies showed that, in enterocyte-like Caco-2 cells, low CPE concentrations cause caspase 3-mediated apoptosis but high CPE concentrations cause necrosis. The recent work published in by Shrestha, Mehdizadeh Gohari, and McClane determined that RIP1 and RIP3 are involved in both CPE-mediated apoptosis and necrosis in Caco-2 cells. Furthermore, mixed lineage kinase-domain (MLKL) oligomerization was shown to be important for necrosis caused by CPE, identifying this necrosis as programmed necroptosis. In addition, calpain activation due to Ca influx through the CPE pore was identified as a critical intermediate step for MLKL oligomerization and, thus, CPE-induced necroptosis. These findings may have applicability to understand the action of some other pore-forming toxins that induce necroptosis and may also be important for understanding CPE action in vivo.