The Optimal Corepressor Function of Nuclear Receptor Corepressor (NCoR) for Peroxisome Proliferator-activated Receptor γ Requires G Protein Pathway Suppressor 2

Repression of peroxisome proliferator-activated receptor gamma (PPAR gamma)-dependent transcription by the nuclear receptor corepressor (NCoR) is important for homeostatic expression of PPAR gamma target genes in vivo. The current model states that NCoR-mediated repression requires its direct interaction with PPAR gamma in the repressive conformation. Previous studies, however, have shown that DNA-bound PPAR gamma is incompatible with a direct, high-affinity association with NCoR because of the inherent ability of PPAR gamma to adopt the active conformation. Here we show that NCoR acquires the ability to repress active PPAR gamma-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 PPAR gamma. In GPS2-deficient mouse embryonic fibroblast cells, loss of GPS2 markedly reduces the corepressor function of NCoR for PPAR gamma, leading to constitutive activation of PPAR gamma target genes and spontaneous adipogenesis of the cells. GPS2, however, is dispensable for repression mediated by unliganded thyroid hormone receptor gamma or aPPAR gamma mutant unable to adopt the active conformation. This study shows that GPS2, although dispensable for the intrinsic repression function of NCoR, can mediate a novel corepressor repression pathway that allows NCoR to directly repress active PPAR gamma-mediated transcription, which is important for the optimal corepressor function of NCoR for PPAR gamma. Interestingly, GPS2-dependent repression specifically targets PPAR gamma but not PPAR alpha or PPAR delta. Therefore, GPS2 may serve as a unique target to manipulate PPAR gamma signaling in diseases.