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Phosphorylation-Dependent Sumoylation Regulates Estrogen-Related Receptor- and - Transcriptional Activity through a Synergy Control Motif

Molecular Oncology Group (A.M.T., B.J.W., X.J.Y., V.G.), McGill University Health Centre, and Departments of Biochemistry (A.M.T., V.G.), Medicine (X.J.Y., V.G.), and Oncology (V.G.), McGill University, Montréal, Québec, Canada H3A 1A1

Address all correspondence and requests for reprints to: Vincent Giguère, Molecular Oncology Group, Room H5–42, McGill University Health Centre, 687 Pine Avenue West, Montréal, Québec, Canada H3A 1A1. E-mail: vincent.giguere{at}mcgill.ca.

Interplay between different posttranslational modifications of transcription factors is an important mechanism to achieve an integrated regulation of gene expression. For the estrogen-related receptors (ERRs) and , regulation by posttranslational modifications is still poorly documented. Here we show that transcriptional repression associated with the ERR amino-terminal domains is mediated through sumoylation at a conserved phospho-sumoyl switch, KxEPxSP, that exists within a larger synergy control motif. Arginine substitution of the sumoylatable lysine residue or alanine substitution of a nearby phosphorylatable serine residue (serine 19 in ERR) increased the transcriptional activity of both ERR and -. In addition, phospho-mimetic substitution of the serine residue with aspartate restored the sumoylation and transcriptional repression activity. The increased transcriptional activity of the sumoylation-deficient mutants was more pronounced in the presence of multiple adjacent ERR response elements. We also identified protein inhibitor of activated signal transducer and activator of transcription y as an interacting partner and a small ubiquitin-related modifier E3 ligase for ERR. Importantly, analysis with a phospho-specific antibody revealed that sumoylation of ERR in mouse liver requires phosphorylation of serine 19. Taken together, these results show that the interplay of phosphorylation and sumoylation in the amino-terminal domain provides an additional mechanism to regulate the transcriptional activity of ERR and -.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERRα  |  ERRγ

Coregulators:   ARIP3  |  PGC-1  |  PIAS3  |  PIAS4

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