T-Cell Death Associated Gene 51 Is a Novel Negative Regulator of PPARγ That Inhibits PPARγRXRα Heterodimer Formation in Adipogenesis

Sumi Kim; Nari Lee; Eui-Soon Park; Hyeongseok Yun; Tae-Uk Ha; Hyoeun Jeon; Jiyeon Yu; Seunga Choi; Bongjin Shin; Jungeun Yu; Sang Dal Rhee; Yongwon Choi; and Jaerang Rho

doi:10.14348/molcells.2020.0143

Mol. Cells https://doi.org/10.14348/molcells.2020.0143

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.

jrrho@cnu.ac.kr

Received July 3, 2020; Revised November 6, 2020; Accepted November 27, 2020.; Published online December 18, 2020.

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