title: O-GlcNAcylation of Orphan Nuclear Receptor Estrogen-Related Receptor γ Promotes Hepatic Gluconeogenesis.
abstract: Estrogen-related receptor γ (ERRγ) is a major positive regulator of hepatic gluconeogenesis. Its transcriptional activity is suppressed by phosphorylation signaled by insulin in the fed state, but whether posttranslational modification alters its gluconeogenic activity in the fasted state is not known. Metabolically active hepatocytes direct a small amount of glucose into the hexosamine biosynthetic pathway, leading to protein O-GlcNAcylation. In this study, we demonstrate that ERRγ is O-GlcNAcylated by O-GlcNAc transferase in the fasted state. This stabilizes the protein by inhibiting proteasome-mediated protein degradation, increasing ERRγ recruitment to gluconeogenic gene promoters. Mass spectrometry identifies two serine residues (S317, S319) present in the ERRγ ligand-binding domain that are O-GlcNAcylated. Mutation of these residues destabilizes ERRγ protein and blocks the ability of ERRγ to induce gluconeogenesis in vivo. The impact of this pathway on gluconeogenesis in vivo was confirmed by the observation that decreasing the amount of O-GlcNAcylated ERRγ by overexpressing the deglycosylating enzyme O-GlcNAcase decreases ERRγ-dependent glucose production in fasted mice. We conclude that O-GlcNAcylation of ERRγ serves as a major signal to promote hepatic gluconeogenesis.
authors.affiliation: National Creative Research Initiatives Center for Nuclear Receptor Signals and Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Jagannath
authors.initials: J
authors.lastname: Misra
authors.affiliation: National Creative Research Initiatives Center for Nuclear Receptor Signals and Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Don-Kyu
authors.initials: DK
authors.lastname: Kim
authors.affiliation: National Creative Research Initiatives Center for Nuclear Receptor Signals and Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Yoon Seok
authors.initials: YS
authors.lastname: Jung
authors.affiliation: Department of Integrated OMICS for Biomedical Science, Yonsei University, Seoul, Republic of Korea.
authors.forename: Han Byeol
authors.initials: HB
authors.lastname: Kim
authors.affiliation: Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
authors.forename: Yong-Hoon
authors.initials: YH
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Kyungpook National University School of Medicine, Deagu, Republic of Korea.
authors.forename: Eun-Kyung
authors.initials: EK
authors.lastname: Yoo
authors.affiliation: Leading-edge Research Center for Drug Discovery and Development and Metabolic Disease, Kyungpook National University, Daegu, Korea.
authors.forename: Byung Gyu
authors.initials: BG
authors.lastname: Kim
authors.affiliation: Medicinal Bioconvergence Research Center Department of Molecular Medicine and Biopharmaceutical Sciences Graduate School of Convergence Science and Technology College of Pharmacy, Seoul National University, Seoul, Korea.
authors.forename: Sunghoon
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Kyungpook National University School of Medicine, Deagu, Republic of Korea.
authors.forename: In-Kyu
authors.initials: IK
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and the Roudebush VA Medical Center, Indianapolis, IN.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Harris
authors.affiliation: Department of Chemistry and Institute of Basic Sciences, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Jeong-Sun
authors.initials: JS
authors.lastname: Kim
authors.affiliation: Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
authors.forename: Chul-Ho
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Department of Integrated OMICS for Biomedical Science, Yonsei University, Seoul, Republic of Korea.
authors.forename: Jin Won
authors.initials: JW
authors.lastname: Cho
authors.affiliation: National Creative Research Initiatives Center for Nuclear Receptor Signals and Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea hsc@chonnam.ac.kr.
authors.forename: Hueng-Sik
authors.initials: HS
authors.lastname: Choi
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005943:Gluconeogenesis / Q000235:genetics / Q000502:physiology*; D006031:Glycosylation; D008099:Liver / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000502:physiology; D011960:Receptors, Estrogen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000737:chemistry / Q000378:metabolism
chemical_list: C490916:Esrrg protein, mouse; D057093:Orphan Nuclear Receptors; D011960:Receptors, Estrogen; D012694:Serine; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase