The optimal corepressor function of nuclear receptor corepressor (NCoR) for peroxisome proliferatoractivated receptor {gamma} requires G-protein pathway suppressor 2 [Protein Structure and Folding]

December 17th, 2014 by Guo, C., Li, Y., Gow, C.-H., Wong, M., Zha, J., Yan, C., Liu, H., Wang, Y., Burris, T. P., Zhang, J.

Repression of peroxisome proliferator-activated receptor γ (PPARγ-dependent transcription by the nuclear receptor corepressor (NCoR) is important for homeostatic expression of PPARγ target genes in vivo. The current model insists that NCoR-mediated repression requires its direct interaction with PPARγ in the repressive conformation. Previous studies, however, have shown that DNA-bound PPARγ is incompatible with a direct, high-affinity association with NCoR due to the inherent ability of PPARγ to adopt the active conformation. Here we show that NCoR acquires the ability to repress active PPARγ-mediated transcription via G-protein pathway suppressor 2 (GPS2), a component of the NCoR corepressor complex. Unlike NCoR, GPS2 can recognize and bind the active state of PPARγ. In GPS2-deficient mouse embryonic fibroblast cells, loss of GPS2 markedly reduces the corepressor function of NCoR for PPARγ, leading to constitutive activation of PPARγ target genes and spontaneous adipogenesis of the cells. GPS2, however, is dispensable for repression mediated by unliganded TRα or a PPARγ mutant unable to adopt the active conformation. This study shows that GPS2, while dispensable for the intrinsic repression function of NCoR, can mediate a novel corepressor repression pathway that allows NCoR to directly repress active PPARγ-mediated transcription, which is important for the optimal corepressor function of NCoR for PPARγ. Interestingly, GPS2-dependent repression specifically targets PPARγ, but not PPARγ or PPARγ. GPS2 may thus serve as a unique target to manipulate PPARγ signaling in diseases.
  • Posted in Journal of Biological Chemistry, Publications
  • Comments Off on The optimal corepressor function of nuclear receptor corepressor (NCoR) for peroxisome proliferatoractivated receptor {gamma} requires G-protein pathway suppressor 2 [Protein Structure and Folding]