title: XBP-1u suppresses autophagy by promoting the degradation of FoxO1 in cancer cells.
abstract: 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.
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research of Ministry of Education, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China. zhaoying0812@ bjmu.edu.cn
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhao
authors.forename: Xue
authors.initials: X
authors.lastname: Li
authors.forename: Mu-Yan
authors.initials: MY
authors.lastname: Cai
authors.forename: Ke
authors.initials: K
authors.lastname: Ma
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: Jingyi
authors.initials: J
authors.lastname: Zhou
authors.forename: Wan
authors.initials: W
authors.lastname: Fu
authors.forename: Fu-Zheng
authors.initials: FZ
authors.lastname: Wei
authors.forename: Lina
authors.initials: L
authors.lastname: Wang
authors.forename: Dan
authors.initials: D
authors.lastname: Xie
authors.forename: Wei-Guo
authors.initials: WG
authors.lastname: Zhu
mesh_terms: D001343:Autophagy; D045744:Cell Line, Tumor; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics*; D004926:Escherichia coli / Q000235:genetics; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005973:Glutamine / Q000172:deficiency*; D006801:Humans; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D020033:Protein Isoforms / Q000172:deficiency / Q000235:genetics; D059748:Proteolysis; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D005973:Glutamine; D046988:Proteasome Endopeptidase Complex