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

• Published in: Molecules and cells 2021, 44(1), , pp.1-12
• Main Authors: Kim, Sumi, Lee, Nari, Park, Eui-Soon, Yun, Hyeongseok, Ha, Tae-Uk, Jeon, Hyoeun, Yu, Jiyeon, Choi, Seunga, Shin, Bongjin, Yu, Jungeun, Rhee, Sang Dal, Choi, Yongwon, Rho, Jaerang
• Format: Article
• Language: English
• Subjects: 3T3-L1 Cells; Adipocytes - cytology; Adipocytes - metabolism; Adipogenesis; Animals; Cell Death; Fatty Acid-Binding Proteins - genetics; Fatty Acid-Binding Proteins - metabolism; Mice; PPAR gamma - metabolism; Promoter Regions, Genetic - genetics; Protein Binding; Protein Multimerization; Retinoid X Receptor alpha - metabolism; T-Lymphocytes - cytology; T-Lymphocytes - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism; 생물학
• ISSN: 1016-8478; 0219-1032
• DOI: 10.14348/molcells.2020.0143

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 death-associated gene 51 (TDAG51) as a novel corepressor 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 proline-glutamine 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 ligand-independent 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.