title: The optimal corepressor function of nuclear receptor corepressor (NCoR) for peroxisome proliferator-activated receptor γ requires G protein pathway suppressor 2.
abstract: 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 states 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 because of 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 thyroid hormone receptor α or a PPARγ 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 PPARγ-mediated transcription, which is important for the optimal corepressor function of NCoR for PPARγ. Interestingly, GPS2-dependent repression specifically targets PPARγ but not PPARα or PPARδ. Therefore, GPS2 may serve as a unique target to manipulate PPARγ signaling in diseases.
authors.affiliation: From the Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, Missouri 63104, the Department of Cancer Biology, Vontz Center for Molecular Studies, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267.
authors.forename: Chun
authors.initials: C
authors.lastname: Guo
authors.affiliation: the Department of Cancer Biology, Vontz Center for Molecular Studies, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267.
authors.forename: Yali
authors.initials: Y
authors.lastname: Li
authors.affiliation: the Department of Cancer Biology, Vontz Center for Molecular Studies, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, the Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City 220, Taiwan.
authors.forename: Chien-Hung
authors.initials: CH
authors.lastname: Gow
authors.affiliation: From the Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, Missouri 63104.
authors.forename: Madeline
authors.initials: M
authors.lastname: Wong
authors.affiliation: From the Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, Missouri 63104.
authors.forename: Jikun
authors.initials: J
authors.lastname: Zha
authors.affiliation: the Department of Cancer Biology, Vontz Center for Molecular Studies, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, the College of Medicine and Forensics, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710049, China, and.
authors.forename: Chunxia
authors.initials: C
authors.lastname: Yan
authors.affiliation: the Infection and Immunity Research Group, Institute of Medical Biology, Chinese Academy of Medical Science, Peking Union Medical College, Kunming, Yunnan 650018, China.
authors.forename: Hongqi
authors.initials: H
authors.lastname: Liu
authors.affiliation: From the Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, Missouri 63104.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: From the Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, Missouri 63104.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Burris
authors.affiliation: From the Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, Missouri 63104, the Department of Cancer Biology, Vontz Center for Molecular Studies, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, jinsongzhang@slu.edu.
authors.forename: Jinsong
authors.initials: J
authors.lastname: Zhang
mesh_terms: D050156:Adipogenesis; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D056971:Nuclear Receptor Co-Repressor 1 / Q000235:genetics / Q000378:metabolism*; D047495:PPAR gamma / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D037021:Thyroid Hormone Receptors alpha / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: C572597:GPS2 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; C539128:Ncor1 protein, mouse; D056971:Nuclear Receptor Co-Repressor 1; D047495:PPAR gamma; D037021:Thyroid Hormone Receptors alpha
keywords: Conformational Change; GPS2; NCoR; Nuclear Receptor; PPARγ; Peroxisome Proliferator-Activated Receptor (PPAR); Thyroid Hormone; Transcription Coactivator; Transcription Corepressor; Transcriptional Repression