Volume 23, No 4, Apr 2013

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 23 Issue 4, April 2013: 491-507

ORIGINAL ARTICLES

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

Ying Zhao¹, Xue Li¹, Mu-Yan Cai², Ke Ma¹, Jing Yang¹, Jingyi Zhou¹, Wan Fu¹,Fu-Zheng Wei¹, Lina Wang¹, Dan Xie² and Wei-Guo Zhu^1,3

¹Key Laboratory of Carcinogenesis and Translational Research of Ministry of Education, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China
²State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong 510060, China
³Peking-Tsinghua University Center for Life Sciences, Peking University, Beijing 100871, China
Correspondence: Wei-Guo Zhu, Ying Zhao(zhuweiguo@bjmu.edu.cn zhaoying0812@bjmu.edu.cn)

Autophagy is activated to maintain cellular energy homeostasis in response to nutrient starvation. However, autophagy is not persistently activated, which is poorly understood at a mechanistic level. Here, we report that turnover of FoxO1 is involved in the dynamic autophagic process caused by glutamine starvation. X-box-binding protein-1u (XBP-1u) has a critical role in FoxO1 degradation by recruiting FoxO1 to the 20S proteasome. In addition, the phosphorylation of XBP-1u by extracellular regulated protein kinases1/2 (ERK1/2) on Ser61 and Ser176 was found to be critical for the increased interaction between XBP-1u and FoxO1 upon glutamine starvation. Furthermore, knockdown of XBP-1u 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-1u 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-1u-induced FoxO1 degradation.

Cell Research (2013) 23:491–507. doi:10.1038/cr.2013.2; published online 1 January 2013

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