XBP-1u suppresses autophagy by promoting the degradation of FoxO1 in cancer cells

Autophagy is activated to maintain cellular energy homeostasis in response to nutrient starvation. However, au- tophagy is not persistently activated, which is poorly understood at a mechanistic level. Here, we report that turn- over of FoxO1 is involved in the dynamic autophagic process caused by glutamine starvation. X-box-binding protein- lu （XBP-lu） has a critical role in FoxO1 degradation by recruiting FoxO1 to the 20S proteasome. In addition, the phosphorylation of XBP-lu by extracellular regulated protein kinasesl/2 （ERK1/2） on Ser61 and Ser176 was found to be critical for the increased interaction between XBP-lu and FoxO1 upon glutamine starvation. Furthermore, knockdown of XBP-lu caused the sustained level of FoxO1 and the persistent activation of autophagy, leading to a significant decrease in cell viability. Finally, the inverse correlation between XBP-lu and FoxO1 expression agrees well with the expression profiles observed in many human cancer tissues. Thus, our findings link the dynamic process of autophagy to XBP-lu-induced FoxO1 degradation.