title: Exchange Factor TBL1 and Arginine Methyltransferase PRMT6 Cooperate in Protecting G Protein Pathway Suppressor 2 (GPS2) from Proteasomal Degradation.
abstract: G protein pathway suppressor 2 (GPS2) is a multifunctional protein involved in the regulation of a number of metabolic organs. First identified as part of the NCoR-SMRT corepressor complex, GPS2 is known to play an important role in the nucleus in the regulation of gene transcription and meiotic recombination. In addition, we recently reported a non-transcriptional role of GPS2 as an inhibitor of the proinflammatory TNFα pathway in the cytosol. Although this suggests that the control of GPS2 localization may be an important determinant of its molecular functions, a clear understanding of GPS2 differential targeting to specific cellular locations is still lacking. Here we show that a fine balance between protein stabilization and degradation tightly regulates GPS2 nuclear function. Our findings indicate that GPS2 is degraded upon polyubiquitination by the E3 ubiquitin ligase Siah2. Unexpectedly, interaction with the exchange factor TBL1 is required to protect GPS2 from degradation, with methylation of GPS2 by arginine methyltransferase PRMT6 regulating the interaction with TBL1 and inhibiting proteasome-dependent degradation. Overall, our findings indicate that regulation of GPS2 by posttranslational modifications provides an effective strategy for modulating its molecular function within the nuclear compartment.
authors.affiliation: From the Biochemistry Department, Boston University School of Medicine, Boston, Massachusetts 02118.
authors.forename: Jiawen
authors.initials: J
authors.lastname: Huang
authors.affiliation: From the Biochemistry Department, Boston University School of Medicine, Boston, Massachusetts 02118.
authors.forename: M Dafne
authors.initials: MD
authors.lastname: Cardamone
authors.affiliation: From the Biochemistry Department, Boston University School of Medicine, Boston, Massachusetts 02118.
authors.forename: Holly E
authors.initials: HE
authors.lastname: Johnson
authors.affiliation: the Chromatin Structure and Cellular Senescence Research Unit, Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Montréal, Quebec H1T 2M4, Canada.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Neault
authors.affiliation: From the Biochemistry Department, Boston University School of Medicine, Boston, Massachusetts 02118.
authors.forename: Michelle
authors.initials: M
authors.lastname: Chan
authors.affiliation: the Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808, and.
authors.forename: Z Elizabeth
authors.initials: ZE
authors.lastname: Floyd
authors.affiliation: the Chromatin Structure and Cellular Senescence Research Unit, Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Montréal, Quebec H1T 2M4, Canada, the Département de Médecine, Université de Montréal, Montréal, Quebec H1T 2M4, Canada.
authors.forename: Frédérick A
authors.initials: FA
authors.lastname: Mallette
authors.affiliation: From the Biochemistry Department, Boston University School of Medicine, Boston, Massachusetts 02118, vperissi@bu.edu.
authors.forename: Valentina
authors.initials: V
authors.lastname: Perissi
mesh_terms: D021581:Active Transport, Cell Nucleus; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism*; D008745:Methylation; D019913:Nuclear Localization Signals; D009687:Nuclear Proteins / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D011484:Protein-Arginine N-Methyltransferases / Q000502:physiology*; D059748:Proteolysis; D015293:Transducin / Q000502:physiology*; D054875:Ubiquitination
chemical_list: C103316:GPS2 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D019913:Nuclear Localization Signals; D009687:Nuclear Proteins; C119542:TBL1X protein, human; C447833:PRMT6 protein, human; D011484:Protein-Arginine N-Methyltransferases; D046988:Proteasome Endopeptidase Complex; D015293:Transducin
keywords: GPS2; PRMT6; Siah2; TBL1; gene expression; protein degradation; protein methylation; transcription corepressor; ubiquitin