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J Biol Chem. 2015 Jul 31;290(31):19044-54. doi: 10.1074/jbc.M115.637660. Epub 2015 Jun 12.

Exchange Factor TBL1 and Arginine Methyltransferase PRMT6 Cooperate in Protecting G Protein Pathway Suppressor 2 (GPS2) from Proteasomal Degradation.

Author information

1
From the Biochemistry Department, Boston University School of Medicine, Boston, Massachusetts 02118.
2
the Chromatin Structure and Cellular Senescence Research Unit, Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Montréal, Quebec H1T 2M4, Canada.
3
the Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808, and.
4
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.
5
From the Biochemistry Department, Boston University School of Medicine, Boston, Massachusetts 02118, vperissi@bu.edu.

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.

KEYWORDS:

GPS2; PRMT6; Siah2; TBL1; gene expression; protein degradation; protein methylation; transcription corepressor; ubiquitin

PMID:
26070566
PMCID:
PMC4521029
DOI:
10.1074/jbc.M115.637660
[Indexed for MEDLINE]
Free PMC Article

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