ERS regulates endometrial epithelial cell autophagy through XBP1s-mediated activation of the PI3K/AKT pathway

Autophagy is a fundamental cellular activity involved in the renewal of cellular components, occurring primarily in cells subjected to physiological remodeling or pathological stimuli. The occurrence of autophagy is closely related to the endoplasmic reticulum (ER), and ER stress (ERS) occurs when ER homeostasis is disrupted. The current study aimed to analyze the molecular mechanisms underlying the effects of ERS on autophagy in goat endometrial epithelial cells (gEECs). We found that rapamycin (an autophagy inducer) induced autophagy and ERS in a time-dependent manner in gEECs which was accompanied by significantly increased expression of the autophagy-related genes ATG5, the LC3II/LC3I and ERS-related genes GRP78, IRE1, ATF6, and XBP1s. PI3K and AKT protein phosphorylation was significantly reduced during gEECs autophagy. Interestingly, TG (ERS activator) significantly inhibited the expression of ATG5 and the LC3II/LC3I and significantly promoted expression of SQSTM1, whereas the ERS inhibitor 4-PBA showed the opposite results. Surprisingly, XBP1s knockdown inhibited the effects of TG. Furthermore, XBP1s overexpression significantly inhibited autophagy whereas XBP1s knockdown increased ATG5 expression and the LC3II/LC3I and decreased SQSTM1 expression in gEECs. Specifically, XBP1s overexpression significantly promoted PI3K and AKT protein phosphorylation while treatment with LY294002 (PI3K/AKT pathway inhibitor) significantly reversed the effect. Similarly, PI3K/AKT pathway activation was significantly inhibited following XBP1s knockdown whereas treatment with SC79 (PI3K/AKT pathway activator) showed the opposite results. Taken together, our data suggest that interactions between ERS and autophagy exist in gEECs. XBP1s, the key effector of ERS, inhibits autophagy in gEECs by promoting the PI3K/AKT pathway in gEECs. These results may contribute to the treatment and prevention of uterine diseases.