Promotion of intestinal epithelial cell apoptosis by enterotoxigenic Escherichia coli via PKA-mediated inhibition of mTORC1 activation.

ABSTRACT

Enterotoxigenic Escherichia coli (ETEC) is the main causative pathogen of diarrhea. It causes acute watery diarrhea that leads to rapid dehydration and prostration within hours. ETEC is still an important cause of neonatal and post-weaning diarrhea in pigs. However, the mechanism underlying ETEC-induced diarrhea is not yet clear. In this study, we investigated these mechanisms and found that the mTORC1 pathway plays a role in the host response to ETEC F4 infection. Specifically, we found that ETEC F4 treatment significantly repressed mTORC1 activity as well as cell proliferation, promoted apoptosis and regulated the expression of diarrhea-related genes via the promotion of PKA-mediated phosphorylation of SIN1, which plays a critical role in the assembly of mTORC2. These findings indicate that PKA is a checkpoint for ETEC-induced diarrhea. In terms of potential therapeutic strategies, we found that ZnSO4 dramatically rescued ETEC F4-induced the inhibition of mTORC1 activity and cell viability and the induction of apoptosis and alterations in the expression of diarrhea-related genes. Thus, the present findings demonstrate that ETEC F4 influences mTORC1 activation by inhibiting the assembly of mTORC2 through PKA-mediated phosphorylation of SIN1. Further, supplementation with ZnSO4 is an effective strategy for blocking the effect of ETEC F4 on mTORC1 activation, and it may have potential clinical applications in the treatment of ETEC F4-induced diarrhea.