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

H Yu, K He, L Wang, J Hu, J Gu, C Zhou… - Journal of cell …, 2015 - journals.biologists.com
H Yu, K He, L Wang, J Hu, J Gu, C Zhou, R Lu, Y Jin
Journal of cell science, 2015journals.biologists.com
ABSTRACT A better understanding of molecular regulation in adipogenesis might help the
development of efficient strategies to cope with obesity-related diseases. Here, we report
that CCAAT/enhancer-binding protein (C/EBP) β and C/EBPδ, two crucial 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 …
Abstract
A better understanding of molecular regulation in adipogenesis might help the development of efficient strategies to cope with obesity-related diseases. Here, we report that CCAAT/enhancer-binding protein (C/EBP) β and C/EBPδ, two crucial 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 and -KD cells. Functionally, knockdown of C/EBPβ eliminates the enhanced adipogenic differentiation in Stk40-KO and -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 and 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.
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