T-Cell Death Associated Gene 51 Is a Novel Negative Regulator of PPARγ That Inhibits PPARγRXRα Heterodimer Formation in Adipogenesis
Sumi Kim 1,4, Nari Lee 1,4, Eui-Soon Park 1, Hyeongseok Yun 1, Tae-Uk Ha 1, Hyoeun Jeon 1, Jiyeon Yu 1, Seunga Choi 1, Bongjin Shin 1, Jungeun Yu 1, Sang Dal Rhee 2, Yongwon Choi 3, and Jaerang Rho 1,*
1Department of Microbiology and Molecular Biology, Chungnam National University, Daejeon 34134, Korea, 2Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Korea, 3Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA, 4These authors contributed equally to this work.
Received July 3, 2020; Revised November 6, 2020; Accepted November 27, 2020.; Published online December 18, 2020.
© Korean Society for Molecular and Cellular Biology. All rights reserved.

ABSTRACT
The nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) is the master transcriptional regulator in adipogenesis. PPARγ forms a heterodimer with another nuclear receptor, retinoid X receptor (RXR), to form an active transcriptional complex, and their transcriptional activity is tightly regulated by the association with either coactivators or corepressors. In this study, we identified T-cell deathassociated gene 51 (TDAG51) as a novel acorepressor of PPARγ-mediated transcriptional regulation. We showed that TDAG51 expression is abundantly maintained in the early stage of adipogenic differentiation. Forced expression of TDAG51 inhibited adipocyte differentiation in 3T3- L1 cells. We found that TDAG51 physically interacts with PPARγ in a ligand-independent manner. In deletion mutant analyses, large portions of the TDAG51 domains, including the pleckstrin homology-like, glutamine repeat and prolineglutamine repeat domains but not the proline-histidine repeat domain, are involved in the interaction with the region between residues 140 and 506, including the DNA binding domain, hinge, ligand binding domain and activation function-2 domain, in PPARγ. The heterodimer formation of PPARγ-RXRα was competitively inhibited in a ligandindependent manner by TDAG51 binding to PPARγ. Thus, our data suggest that TDAG51, which could determine adipogenic cell fate, acts as a novel negative regulator of PPARγ by blocking RXRα recruitment to the PPARγ-RXRα heterodimer complex in adipogenesis.
Keywords: adipocyte differentiation, adipogenesis, pleckstrin homology-like domain A family, peroxisome proliferatoractivated receptor gamma, retinoid X receptor alpha, T-cell death-associated gene 51
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31 December 2020 Volume 43,
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