Endoplasmic reticulum stress-induced apoptosis in intestinal epithelial cells: a feed-back regulation by mechanistic target of rapamycin complex 1 (mTORC1)

摘要

Background:Endoplasmic reticulum (ER) stress is associated with multiple pathological processes of intestinal diseases.Despite a critical role of mechanistic target of rapamycin complex 1 (mTORC1) in regulating cellular stress response,the crosstalk between mTORC1 and ER stress signaling and its contribution to the intestinal barrier function is unknown.Results:In the present study,we showed that intestinal epithelial cells (IEC-6) incubated with tunicamycin led to caspase-3-dependent apoptotic cell death.The induction of cell death was accompanied by activation of unfolded protein response as evidenced by increased protein levels for BiP,p-IRE1α,p-elF2α,p-JNK,and CHOP.Further study demonstrated that tunicamycin-induced cell death was enhanced by rapamycin,a specific inhibitor of mTORC1.Consistently,tunicamycin decreased transepithelial electrical resistance (TEER) and increased permeability of the cells.These effects of tunicamycin were exacerbated by mTORC1 inhibitor.Conclusions:Taken together,the data presented here identified a previously unknown crosstalk between an unfold protein response and mTORC1 signaling in the intestinal epithelium.This feed-back loop regulation on ER stress signaling by mTORC1 is critical for cell survival and intestinal permeability in epithelial cells.