On the Interaction of Clostridium perfringens Enterotoxin with Claudins

Abstract

Clostridium perfringens causes one of the most common foodborne illnesses, which is largely mediated by the Clostridium perfringens enterotoxin (CPE). The toxin consists of two functional domains. The N-terminal region mediates the cytotoxic effect through pore formation in the plasma membrane of the mammalian host cell. The C-terminal region (cCPE) binds to the second extracellular loop of a subset of claudins. Claudin-3 and claudin-4 have been shown to be receptors for CPE with very high affinity. The toxin binds with weak affinity to claudin-1 and -2 but contribution of these weak binding claudins to CPE-mediated disease is questionable. cCPE is not cytotoxic, however, it is a potent modulator of tight junctions. This review describes recent progress in the molecular characterization of the cCPE-claudin interaction using mutagenesis, in vitro binding assays and permeation studies. The results promote the development of recombinant cCPE-proteins and CPE-based peptidomimetics to modulate tight junctions for improved drug delivery or to treat tumors overexpressing claudins.

A Synthetic Peptide Corresponding to the Extracellular Loop 2 Region of Claudin-4 Protects against Clostridium perfringens Enterotoxin In Vitro and In Vivo

“…Consistent with previous reports that ECL-2 contains most or all of the CPE binding activity for claudin receptors (25,30,32), two findings indicate that the mechanism of protection provided by the claudin-4 ECL-2 peptide involved a reduction in CPE binding to Caco-2 cells. First, Western blotting directly demonstrated a claudin-4 ECL-2 peptide-induced inhibition of CPE binding to Caco-2 cells.…”

“…More recently, CPE binding activity was specifically mapped to the ECL-2 region of receptor claudins (30). The ECL-2 region forms a helix-turn-helix (31)(32)(33)(34) that docks into a pocket in the C-terminal CPE binding domain (29,31,(35)(36)(37). Recent work identified ECL-2 sequence variations that dictate whether a claudin can bind CPE, as well as delineating the ECL-2 determinants that define the affinity of this binding.…”

Estrogen-dependent expression and subcellular localization of the tight junction protein claudin-4 in HEC-1A endometrial cancer cells

“…To prevent wide-spread cytolysis by use of this therapy, researchers have focused on a non-cytotoxic C-terminal fragment of CPE to specifically bind CLDN-3 or -4, altering the TJ, and subsequently allowing for better drug absorption by affected cells (31). Furthermore, the changes in CLDN-3 and -4 expression in certain cancers have suggested that these proteins may be potential prognostic markers.…”

Host cell-induced signaling causesClostridium perfringensto upregulate production of toxins important for intestinal infections

“…Once present in the intestinal lumen, CPE binds to enterocytes via receptors that include certain members of the claudin tight junction protein family. 11,12 Bound CPE then oligomerizes into a hexameric prepore on the host cell membrane surface. 13 This prepore rapidly inserts into membranes to form an active pore that increases Ca 2+ influx, which then kills enterocytes via either oncosis or apoptosis.…”