Endoplasmic reticulum stress-induced apoptosis in intestinal epithelial cells: a feed-back regulation by mechanistic target of rapamycin complex 1 (mTORC1).
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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-IRE1, p-eIF2, 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 tunicamycinwere exacerbated by mTORC1 inhibitor. CONCLUSIONS: Taken together, the data presented here identified a previously unknown crosstalk between anunfold 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.
