title: 20-Hydroxyecdysone activates Forkhead box O to promote proteolysis during Helicoverpa armigera molting.
abstract: Insulin inhibits transcription factor Forkhead box O (FoxO) activity, and the steroid hormone 20-hydroxyecdysone (20E) activates FoxO; however, the mechanism is unclear. We hypothesized that 20E upregulates phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase (PTEN) expression to activate FoxO, thereby promoting proteolysis during molting in the lepidopteran insect Helicoverpa armigera. FoxO expression is increased during molting and metamorphosis. The knockdown of FoxO in fifth instar larvae results in larval molting failure. 20E inhibits FoxO phosphorylation, resulting in FoxO nuclear translocation. Insulin, via Akt, induces FoxO phosphorylation and cytoplasmic localization. 20E represses insulin-induced Akt phosphorylation and FoxO phosphorylation. 20E, via ecdysone receptor B1 (EcRB1) and the ultraspiracle protein (USP1), upregulates PTEN expression, which represses Akt phosphorylation, thereby repressing FoxO phosphorylation. The non-phosphorylated FoxO enters the nucleus and attaches to a FoxO-binding element in the upstream region of the Broad isoform 7 (BrZ7) gene to regulate BrZ7 transcription under 20E induction. 20E upregulates FoxO expression via EcRB1 and USP1. FoxO regulation of BrZ7 expression regulates Carboxypeptidase A expression for final proteolysis during insect molting. Hence, 20E activates FoxO via upregulating PTEN expression to counteract insulin activity and promote proteolysis.
authors.affiliation: Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Jinan, Shandong 250100, China.
authors.forename: Mei-Juan
authors.initials: MJ
authors.lastname: Cai
authors.affiliation: Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Jinan, Shandong 250100, China.
authors.forename: Wen-Li
authors.initials: WL
authors.lastname: Zhao
authors.affiliation: Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Jinan, Shandong 250100, China.
authors.forename: Yu-Pu
authors.initials: YP
authors.lastname: Jing
authors.affiliation: Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Jinan, Shandong 250100, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Song
authors.affiliation: Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Jinan, Shandong 250100, China.
authors.forename: Xiao-Qian
authors.initials: XQ
authors.lastname: Zhang
authors.affiliation: Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Jinan, Shandong 250100, China.
authors.forename: Jin-Xing
authors.initials: JX
authors.lastname: Wang
authors.affiliation: Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Jinan, Shandong 250100, China xfzhao@sdu.edu.cn.
authors.forename: Xiao-Fan
authors.initials: XF
authors.lastname: Zhao
mesh_terms: D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D017124:Conserved Sequence; D004441:Ecdysterone / Q000494:pharmacology*; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D055785:Gene Knockdown Techniques; D019476:Insect Proteins / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology; D007814:Larva / Q000502:physiology; D008954:Models, Biological; D018978:Molting / Q000187:drug effects*; D009036:Moths / Q000187:drug effects / Q000235:genetics / Q000254:growth & development*; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D051858:Forkhead Transcription Factors; D019476:Insect Proteins; D007328:Insulin; D014157:Transcription Factors; D004441:Ecdysterone; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase
keywords: Cotton bollworm; Forkhead box O; PTEN; Protein kinase B/Akt; Proteolysis; Steroid hormone