title: Stk40 represses adipogenesis through translational control of CCAAT/enhancer-binding proteins.
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.
authors.affiliation: Laboratory of Molecular Developmental Biology, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.
authors.forename: Hongyao
authors.initials: H
authors.lastname: Yu
authors.affiliation: Laboratory of Molecular Developmental Biology, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.
authors.forename: Ke
authors.initials: K
authors.lastname: He
authors.affiliation: Laboratory of Molecular Developmental Biology, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.
authors.forename: Lina
authors.initials: L
authors.lastname: Wang
authors.affiliation: Laboratory of Molecular Developmental Biology, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Hu
authors.affiliation: Laboratory of Molecular Developmental Biology, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.
authors.forename: Junjie
authors.initials: J
authors.lastname: Gu
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
authors.forename: Chenlin
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Lu
authors.affiliation: Laboratory of Molecular Developmental Biology, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China yjin@sibs.ac.cn.
authors.forename: Ying
authors.initials: Y
authors.lastname: Jin
mesh_terms: D041721:3T3-L1 Cells; D048868:Adaptor Proteins, Signal Transducing; D050156:Adipogenesis / Q000235:genetics*; D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics*; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000235:genetics*; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D002460:Cell Line; D039561:Eukaryotic Initiation Factor-4E / Q000235:genetics; D039642:Eukaryotic Initiation Factors; D055786:Gene Knockout Techniques; D050356:Lipid Metabolism / Q000235:genetics; D051379:Mice; D009765:Obesity / Q000235:genetics; D010750:Phosphoproteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000235:genetics; D014176:Protein Biosynthesis / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D022782:CCAAT-Enhancer-Binding Protein-beta; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C499527:Eif4ebp1 protein, mouse; D039561:Eukaryotic Initiation Factor-4E; D039642:Eukaryotic Initiation Factors; D010750:Phosphoproteins; C000601282:eIF4E protein, mouse; D051743:CCAAT-Enhancer-Binding Protein-delta; D017346:Protein Serine-Threonine Kinases; C547661:Stk40 protein, mouse
keywords: 4E-BP1; Adipogenesis; C/EBP; Stk40; eIF4E