Journal of Biological Chemistry
Volume 293, Issue 44, 2 November 2018, Pages 17119-17134
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Cell Biology
The TEA domain family transcription factor TEAD4 represses murine adipogenesis by recruiting the cofactors VGLL4 and CtBP2 into a transcriptional complex

https://doi.org/10.1074/jbc.RA118.003608Get rights and content
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The Hippo signaling pathway is known to play an important role in multiple physiological processes, including adipogenesis. However, whether the downstream components of the Hippo pathway are involved in adipogenesis remains unknown. Here we demonstrate that the TEA domain family (TEAD) transcription factors are essential for adipogenesis in murine 3T3-L1 preadipocytes. Knockdown of TEAD1–4 stimulated adipogenesis and increased the expression of adipocyte markers in these cells. Interestingly, we found that the TEAD4 knockdown–mediated adipogenesis proceeded in a Yes-associated protein (YAP)/TAZ (Wwtr1)–independent manner and that adipogenesis suppression in WT cells involved formation of a ternary complex comprising TEAD4 and the transcriptional cofactors C-terminal binding protein 2 (CtBP2) and vestigial-like family member 4 (VGLL4). VGLL4 acted as an adaptor protein that enhanced the interaction between TEAD4 and CtBP2, and this TEAD4–VGLL4–CtBP2 ternary complex dynamically existed at the early stage of adipogenesis. Finally, we verified that TEAD4 directly targets the promoters of major adipogenesis transcription factors such as peroxisome proliferator–activated receptor γ (PPARγ) and adiponectin, C1Q, and collagen domain–containing (Adipoq) during adipogenesis. These findings reveal critical insights into the role of the TEAD4–VGLL4–CtBP2 transcriptional repressor complex in suppression of adipogenesis in murine preadipocytes.

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This work was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB19000000), The National Key Research and Development Program of China (2017YFA0103601), The National Natural Science Foundation of China (31625017 and 31530043), the Cross- and Co-operation in Science and Technology Innovation Team Project of the Chinese Academy of Sciences, and the Chinese Academy of Sciences/SAFEA International Partnership Program for Creative Research Teams. The authors declare that they have no conflicts of interest with the contents of this article.

This article contains Figs. S1–S6 and Tables S1–S3.

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The abbreviations used are:

    PPAR

    peroxisome proliferator–activated receptor

    C/EBP

    CCAAT/enhancer-binding protein

    KLF

    Krüppel-like factor

    CtBP

    C-terminal binding protein

    YAP

    Yes-associated protein

    VGLL

    vestigial-like

    qPCR

    quantitative PCR

    shRNA

    short hairpin RNA

    KEGG

    Kyoto Encyclopedia of Genes and Genomes

    IP

    immunoprecipitation

    NLS

    nuclear localization sequence

    IVTT

    in vitro transcription and translation

    aa

    amino acids

    HA

    hemagglutinin

    GST

    glutathione S-transferase

    cDNA

    complementary DNA

    DMEM

    Dulbecco's modified Eagle's medium

    FBS

    fetal bovine serum

    GAPDH

    glyceraldehyde-3-phosphate dehydrogenase

    IBMX

    3-isobutyl-1-methylxanthine

    RT-qPCR

    quantitative real-time PCR

    MBP

    maltose-binding protein.