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《Journal of Cell Science》 0: (2015)

Stk40 represses adipogenesis through translational control of CCAAT/enhancer-binding proteins

Yu, Hongyao; He, Ke; Wang, Lina; Hu, Jing; Gu, Junjie; Zhou, Chenlin; Lu, Rui; Jin, Ying

Abstract:

A better understanding of molecular regulation in adipogenesis may help develop efficient strategies to cope with obesity-related diseases. Here, we report CCAAT/enhancer binding protein (C/EBP) β and δ, two critical pro-adipogenic transcription factors, are controlled at a translational level by serine/threonine kinase 40 (Stk40). Genetic knockout (KO) or knockdown (KD) of Stk40 leads to increased protein levels of C/EBP proteins and adipocyte differentiation in mouse embryonic fibroblasts (MEFs), fetal liver stromal cells, and mesenchymal stem cells (MSCs). In contrast, overexpression of Stk40 abolishes the enhanced C/EBP protein translation and adipogenesis observed in Stk40-KO/KD cells. Functionally, knockdown of C/EBPβ eliminates the enhanced adipogenic differentiation in Stk40-KO/KD cells substantially. Mechanistically, deletion of Stk40 enhances phosphorylation of eIF4E-binding protein 1, leading to increased eIF4E-dependent translation of C/EBPβ and C/EBPδ. Knockdown of eIF4E in MSCs decreases translation of C/EBP proteins. Moreover, Stk40-KO fetal livers display an increased adipogenic program and aberrant lipid/steroid metabolism. Collectively, our study uncovers a new repressor of C/EBP protein translation as well as adipogenesis and provides new insights into the molecular mechanism underpinning the adipogenic program.