The optimal corepressor function of nuclear receptor corepressor (NCoR) for peroxisome proliferator-activated receptor ? requires G protein pathway suppressor 2.

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

SUBMITTER: Guo C 

PROVIDER: S-EPMC4319032 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature