Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
권호 표지
DOI QR코드

DOI QR Code

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

  • Kim, Sumi (Department of Microbiology and Molecular Biology, Chungnam National University) ;
  • Lee, Nari (Department of Microbiology and Molecular Biology, Chungnam National University) ;
  • Park, Eui-Soon (Department of Microbiology and Molecular Biology, Chungnam National University) ;
  • Yun, Hyeongseok (Department of Microbiology and Molecular Biology, Chungnam National University) ;
  • Ha, Tae-Uk (Department of Microbiology and Molecular Biology, Chungnam National University) ;
  • Jeon, Hyoeun (Department of Microbiology and Molecular Biology, Chungnam National University) ;
  • Yu, Jiyeon (Department of Microbiology and Molecular Biology, Chungnam National University) ;
  • Choi, Seunga (Department of Microbiology and Molecular Biology, Chungnam National University) ;
  • Shin, Bongjin (Department of Microbiology and Molecular Biology, Chungnam National University) ;
  • Yu, Jungeun (Department of Microbiology and Molecular Biology, Chungnam National University) ;
  • Rhee, Sang Dal (Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology) ;
  • Choi, Yongwon (Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine) ;
  • Rho, Jaerang (Department of Microbiology and Molecular Biology, Chungnam National University)
  • Received : 2020.07.03
  • Accepted : 2020.11.27
  • Published : 2021.01.31
Download PDF
⟨ Previous Next ⟩

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 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.

Keywords

Acknowledgement

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) and was funded by the Ministry of Education (NRF-2017R1A2B4007327, 2019R1A2C1084311, 2019M3F6A1109486) and by the research fund of Chungnam National University.

References

  1. Ahmadian, M., Suh, J.M., Hah, N., Liddle, C., Atkins, A.R., Downes, M., and Evans, R.M. (2013). PPARgamma signaling and metabolism: the good, the bad and the future. Nat. Med. 19, 557-566. https://doi.org/10.1038/nm.3159
  2. Armoni, M., Harel, C., Karni, S., Chen, H., Bar-Yoseph, F., Ver, M.R., Quon, M.J., and Karnieli, E. (2006). FOXO1 represses peroxisome proliferatoractivated receptor-gamma1 and -gamma2 gene promoters in primary adipocytes. A novel paradigm to increase insulin sensitivity. J. Biol. Chem. 281, 19881-19891. https://doi.org/10.1074/jbc.M600320200
  3. Basseri, S., Lhotak, S., Fullerton, M.D., Palanivel, R., Jiang, H., Lynn, E.G., Ford, R.J., Maclean, K.N., Steinberg, G.R., and Austin, R.C. (2013). Loss of TDAG51 results in mature-onset obesity, hepatic steatosis, and insulin resistance by regulating lipogenesis. Diabetes 62, 158-169. https://doi.org/10.2337/db12-0256
  4. Burton, G.R., Nagarajan, R., Peterson, C.A., and McGehee, R.E., Jr. (2004). Microarray analysis of differentiation-specific gene expression during 3T3-L1 adipogenesis. Gene 329, 167-185. https://doi.org/10.1016/j.gene.2003.12.012
  5. Chandra, V., Huang, P., Hamuro, Y., Raghuram, S., Wang, Y., Burris, T.P., and Rastinejad, F. (2008). Structure of the intact PPAR-gamma-RXR- nuclear receptor complex on DNA. Nature 456, 350-356. https://doi.org/10.1038/nature07413
  6. Chen, Y., Takikawa, M., Tsutsumi, S., Yamaguchi, Y., Okabe, A., Shimada, M., Kawase, T., Sada, A., Ezawa, I., Takano, Y., et al. (2018). PHLDA1, another PHLDA family protein that inhibits Akt. Cancer Sci. 109, 3532-3542. https://doi.org/10.1111/cas.13796
  7. Dowell, P., Otto, T.C., Adi, S., and Lane, M.D. (2003). Convergence of peroxisome proliferator-activated receptor gamma and Foxo1 signaling pathways. J. Biol. Chem. 278, 45485-45491. https://doi.org/10.1074/jbc.M309069200
  8. Elberg, G., Gimble, J.M., and Tsai, S.Y. (2000). Modulation of the murine peroxisome proliferator-activated receptor γ2 promoter activity by CCAAT/enhancer-binding proteins. J. Biol. Chem. 275, 27815-27822. https://doi.org/10.1074/jbc.M003593200
  9. Fan, W., Imamura, T., Sonoda, N., Sears, D.D., Patsouris, D., Kim, J.J., and Olefsky, J.M. (2009). FOXO1 transrepresses peroxisome proliferatoractivated receptor gamma transactivation, coordinating an insulininduced feed-forward response in adipocytes. J. Biol. Chem. 284, 12188-12197. https://doi.org/10.1074/jbc.M808915200
  10. Fearon, A.E., Carter, E.P., Clayton, N.S., Wilkes, E.H., Baker, A.M., Kapitonova, E., Bakhouche, B.A., Tanner, Y., Wang, J., Gadaleta, E., et al. (2018). PHLDA1 mediates drug resistance in receptor tyrosine kinase-driven cancer. Cell Rep. 22, 2469-2481. https://doi.org/10.1016/j.celrep.2018.02.028
  11. Gehring, W.J., Affolter, M., and Burglin, T. (1994). Homeodomain proteins. Annu. Rev. Biochem. 63, 487-526. https://doi.org/10.1146/annurev.bi.63.070194.002415
  12. Hauser, S., Adelmant, G., Sarraf, P., Wright, H.M., Mueller, E., and Spiegelman, B.M. (2000). Degradation of the peroxisome proliferator-activated receptor gamma is linked to ligand-dependent activation. J. Biol. Chem. 275, 18527-18533. https://doi.org/10.1074/jbc.M001297200
  13. Hayashida, N., Inouye, S., Fujimoto, M., Tanaka, Y., Izu, H., Takaki, E., Ichikawa, H., Rho, J., and Nakai, A. (2006). A novel HSF1-mediated death pathway that is suppressed by heat shock proteins. EMBO J. 25, 4773-4783. https://doi.org/10.1038/sj.emboj.7601370
  14. Hossain, G.S., Lynn, E.G., Maclean, K.N., Zhou, J., Dickhout, J.G., Lhotak, S., Trigatti, B., Capone, J., Rho, J., Tang, D., et al. (2013). Deficiency of TDAG51 protects against atherosclerosis by modulating apoptosis, cholesterol efflux, and peroxiredoxin-1 expression. J. Am. Heart Assoc. 2, e000134. https://doi.org/10.1161/JAHA.113.000134
  15. Hu, E., Kim, J.B., Sarraf, P., and Spiegelman, B.M. (1996). Inhibition of adipogenesis through MAP kinase-mediated phosphorylation of PPARgamma. Science 274, 2100-2103. https://doi.org/10.1126/science.274.5295.2100
  16. Iankova, I., Petersen, R.K., Annicotte, J.S., Chavey, C., Hansen, J.B., Kratchmarova, I., Sarruf, D., Benkirane, M., Kristiansen, K., and Fajas, L. (2006). Peroxisome proliferator-activated receptor gamma recruits the positive transcription elongation factor b complex to activate transcription and promote adipogenesis. Mol. Endocrinol. 20, 1494-1505. https://doi.org/10.1210/me.2005-0222
  17. Jiao, H.W., Jia, X.X., Zhao, T.J., Rong, H., Zhang, J.N., Cheng, Y., Zhu, H.P., Xu, K.L., Guo, S.Y., Shi, Q.Y., et al. (2016). Up-regulation of TDAG51 is a dependent factor of LPS-induced RAW264.7 macrophages proliferation and cell cycle progression. Immunopharmacol. Immunotoxicol. 38, 124-130. https://doi.org/10.3109/08923973.2016.1138968
  18. Johnson, E.O., Chang, K.H., de Pablo, Y., Ghosh, S., Mehta, R., Badve, S., and Shah, K. (2011). PHLDA1 is a crucial negative regulator and effector of Aurora A kinase in breast cancer. J. Cell Sci. 124, 2711-2722. https://doi.org/10.1242/jcs.084970
  19. Juge-Aubry, C., Pernin, A., Favez, T., Burger, A.G., Wahli, W., Meier, C.A., and Desvergne, B. (1997). DNA binding properties of peroxisome proliferator-activated receptor subtypes on various natural peroxisome proliferator response elements. Importance of the 5'-flanking region. J. Biol. Chem. 272, 25252-25259. https://doi.org/10.1074/jbc.272.40.25252
  20. Kamata, M., Okitsu, Y., Fujiwara, T., Kanehira, M., Nakajima, S., Takahashi, T., Inoue, A., Fukuhara, N., Onishi, Y., Ishizawa, K., et al. (2014). GATA2 regulates differentiation of bone marrow-derived mesenchymal stem cells. Haematologica 99, 1686-1696. https://doi.org/10.3324/haematol.2014.105692
  21. Kim, J.I., Kaufman, R.J., Back, S.H., and Moon, J.Y. (2019). Development of a reporter system monitoring regulated intramembrane proteolysis of the transmembrane bZIP transcription factor ATF6alpha. Mol. Cells 42, 783-793. https://doi.org/10.14348/molcells.2019.0104
  22. Kim, T.H., Kim, H., Park, J.M., Im, S.S., Bae, J.S., Kim, M.Y., Yoon, H.G., Cha, J.Y., Kim, K.S., and Ahn, Y.H. (2009). Interrelationship between liver X receptor alpha, sterol regulatory element-binding protein-1c, peroxisome proliferator-activated receptor gamma, and small heterodimer partner in the transcriptional regulation of glucokinase gene expression in liver. J. Biol. Chem. 284, 15071-15083. https://doi.org/10.1074/jbc.M109.006742
  23. Kroker, A.J. and Bruning, J.B. (2015). Review of the structural and dynamic mechanisms of PPARgamma partial agonism. PPAR Res. 2015, 816856. https://doi.org/10.1155/2015/816856
  24. Lefterova, M.I. and Lazar, M.A. (2009). New developments in adipogenesis. Trends Endocrinol. Metab. 20, 107-114. https://doi.org/10.1016/j.tem.2008.11.005
  25. Li, G., Wang, X., Hibshoosh, H., Jin, C., and Halmos, B. (2014). Modulation of ErbB2 blockade in ErbB2-positive cancers: the role of ErbB2 Mutations and PHLDA1. PLoS One 9, e106349. https://doi.org/10.1371/journal.pone.0106349
  26. Miard, S. and Fajas, L. (2005). Atypical transcriptional regulators and cofactors of PPARgamma. Int. J. Obes. (Lond.) 29 Suppl 1, S10-S12. https://doi.org/10.1038/sj.ijo.0802906
  27. Nagai, M.A. (2016). Pleckstrin homology-like domain, family A, member 1 (PHLDA1) and cancer. Biomed. Rep. 4, 275-281. https://doi.org/10.3892/br.2016.580
  28. Nakae, J., Kitamura, T., Kitamura, Y., Biggs, W.H., 3rd, Arden, K.C., and Accili, D. (2003). The forkhead transcription factor Foxo1 regulates adipocyte differentiation. Dev. Cell 4, 119-129. https://doi.org/10.1016/S1534-5807(02)00401-X
  29. Nishizawa, H., Yamagata, K., Shimomura, I., Takahashi, M., Kuriyama, H., Kishida, K., Hotta, K., Nagaretani, H., Maeda, N., Matsuda, M., et al. (2002). Small heterodimer partner, an orphan nuclear receptor, augments peroxisome proliferator-activated receptor gamma transactivation. J. Biol. Chem. 277, 1586-1592. https://doi.org/10.1074/jbc.M104301200
  30. Park, C.G., Lee, S.Y., Kandala, G., Lee, S.Y., and Choi, Y. (1996). A novel gene product that couples TCR signaling to Fas(CD95) expression in activation-induced cell death. Immunity 4, 583-591. https://doi.org/10.1016/S1074-7613(00)80484-7
  31. Park, E.S., Choi, S., Shin, B., Yu, J., Hwang, J.M., Yun, H., Chung, Y.H., Choi, J.S., Choi, Y., and Rho, J. (2015). Tumor necrosis factor (TNF) receptor-associated factor (TRAF)-interacting protein (TRIP) negatively regulates the TRAF2 ubiquitin-dependent pathway by suppressing the TRAF2-sphingosine 1-phosphate (S1P) interaction. J. Biol. Chem. 290, 9660-9673. https://doi.org/10.1074/jbc.M114.609685
  32. Park, E.S., Kim, J., Ha, T.U., Choi, J.S., Soo Hong, K., and Rho, J. (2013). TDAG51 deficiency promotes oxidative stress-induced apoptosis through the generation of reactive oxygen species in mouse embryonic fibroblasts. Exp. Mol. Med. 45, e35. https://doi.org/10.1038/emm.2013.67
  33. Park, M.J., Kong, H.J., Kim, H.Y., Kim, H.H., Kim, J.H., and Cheong, J.H. (2007). Transcriptional repression of the gluconeogenic gene PEPCK by the orphan nuclear receptor SHP through inhibitory interaction with C/EBPalpha. Biochem. J. 402, 567-574. https://doi.org/10.1042/BJ20061549
  34. Pascual, G., Fong, A.L., Ogawa, S., Gamliel, A., Li, A.C., Perissi, V., Rose, D.W., Willson, T.M., Rosenfeld, M.G., and Glass, C.K. (2005). A SUMOylationdependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma. Nature 437, 759-763. https://doi.org/10.1038/nature03988
  35. Qiao, L. and Shao, J. (2006). SIRT1 regulates adiponectin gene expression through Foxo1-C/enhancer-binding protein alpha transcriptional complex. J. Biol. Chem. 281, 39915-39924. https://doi.org/10.1074/jbc.M607215200
  36. Rosen, E., Eguchi, J., and Xu, Z. (2009). Transcriptional targets in adipocyte biology. Expert Opin. Ther. Targets 13, 975-986. https://doi.org/10.1517/14728220903039706
  37. Rosen, E.D., Hsu, C.H., Wang, X., Sakai, S., Freeman, M.W., Gonzalez, F.J., and Spiegelman, B.M. (2002). C/EBPalpha induces adipogenesis through PPARgamma: a unified pathway. Genes Dev. 16, 22-26. https://doi.org/10.1101/gad.948702
  38. Saladin, R., Fajas, L., Dana, S., Halvorsen, Y.D., Auwerx, J., and Briggs, M. (1999). Differential regulation of peroxisome proliferator activated receptor gamma1 (PPARgamma1) and PPARgamma2 messenger RNA expression in the early stages of adipogenesis. Cell Growth Differ. 10, 43-48.
  39. Sarjeant, K. and Stephens, J.M. (2012). Adipogenesis. Cold Spring Harb. Perspect. Biol. 4, a008417. https://doi.org/10.1101/cshperspect.a008417
  40. Scheffzek, K. and Welti, S. (2012). Pleckstrin homology (PH) like domains - versatile modules in protein-protein interaction platforms. FEBS Lett. 586, 2662-2673. https://doi.org/10.1016/j.febslet.2012.06.006
  41. Son, H.E., Min, H.Y., Kim, E.J., and Jang, W.G. (2020). Fat mass and obesityassociated (FTO) stimulates osteogenic differentiation of C3H10T1/2 cells by inducing mild endoplasmic reticulum stress via a positive feedback loop with p-AMPK. Mol. Cells 43, 58-65. https://doi.org/10.14348/molcells.2019.0136
  42. Tanaka, T., Yoshida, N., Kishimoto, T., and Akira, S. (1997). Defective adipocyte differentiation in mice lacking the C/EBPbeta and/or C/EBPdelta gene. EMBO J. 16, 7432-7443. https://doi.org/10.1093/emboj/16.24.7432
  43. Tong, Q., Dalgin, G., Xu, H., Ting, C.N., Leiden, J.M., and Hotamisligil, G.S. (2000). Function of GATA transcription factors in preadipocyte-adipocyte transition. Science 290, 134-138. https://doi.org/10.1126/science.290.5489.134
  44. Tontonoz, P., Hu, E., Graves, R.A., Budavari, A.I., and Spiegelman, B.M. (1994). mPPAR gamma 2: tissue-specific regulator of an adipocyte enhancer. Genes Dev. 8, 1224-1234. https://doi.org/10.1101/gad.8.10.1224
  45. Waite, K.J., Floyd, Z.E., Arbour-Reily, P., and Stephens, J.M. (2001). Interferon-gamma-induced regulation of peroxisome proliferator-activated receptor gamma and STATs in adipocytes. J. Biol. Chem. 276, 7062-7068. https://doi.org/10.1074/jbc.M007894200
  46. Wu, Z., Bucher, N.L., and Farmer, S.R. (1996). Induction of peroxisome proliferator-activated receptor gamma during the conversion of 3T3 fibroblasts into adipocytes is mediated by C/EBPbeta, C/EBPdelta, and glucocorticoids. Mol. Cell. Biol. 16, 4128-4136. https://doi.org/10.1128/MCB.16.8.4128
  47. Wu, Z., Rosen, E.D., Brun, R., Hauser, S., Adelmant, G., Troy, A.E., McKeon, C., Darlington, G.J., and Spiegelman, B.M. (1999). Cross-regulation of C/EBP alpha and PPAR gamma controls the transcriptional pathway of adipogenesis and insulin sensitivity. Mol. Cell 3, 151-158. https://doi.org/10.1016/S1097-2765(00)80306-8
  48. Xiao, H. and Jeang, K.T. (1998). Glutamine-rich domains activate transcription in yeast Saccharomyces cerevisiae. J. Biol. Chem. 273, 22873-22876. https://doi.org/10.1074/jbc.273.36.22873
  49. Yamagata, K., Daitoku, H., Shimamoto, Y., Matsuzaki, H., Hirota, K., Ishida, J., and Fukamizu, A. (2004). Bile acids regulate gluconeogenic gene expression via small heterodimer partner-mediated repression of hepatocyte nuclear factor 4 and Foxo1. J. Biol. Chem. 279, 23158-23165. https://doi.org/10.1074/jbc.M314322200
  50. Yu, J., Yun, H., Shin, B., Kim, Y., Park, E.S., Choi, S., Yu, J., Amarasekara, D.S., Kim, S., Inoue, J., et al. (2016). Interaction of tumor necrosis factor receptorassociated factor 6 (TRAF6) and Vav3 in the receptor activator of nuclear factor kappaB (RANK) signaling complex enhances osteoclastogenesis. J. Biol. Chem. 291, 20643-20660. https://doi.org/10.1074/jbc.M116.728303

Cited by

  1. Pax5 Negatively Regulates Osteoclastogenesis through Downregulation of Blimp1 vol.22, pp.4, 2021, https://doi.org/10.3390/ijms22042097