RSUME enhances Glucocorticoid Receptor SUMOylation and transcriptional activity

J DRUKER; AC LIBERMAN; J GEREZ; M PÁEZ-PEREDA; T REIN; JA IÑIGUEZ-LLUHÍ; F HOLSBOER; E ARZT

Simposio; Frontiers in BioScience- Joint Symposium of the Max Planck Society and the Ministry of Science, Technology and Innovation.; 2012

Glucocorticoid receptor (GR) activity is modulated by post-translational modifications including phosphorylation, acetylation, ubiquitylation, and SUMOylation. It has been reported that GR has three SUMOylation sites: lysine (K) 297 and K313 in the N-terminal domain (NTD) and K721 within the ligand binding domain (LBD). SUMOylation of the NTD sites are responsible for the negative effect of the synergy control (SC) motifs on GR transcriptional activity on promoters with closely spaced GR binding sites. In contrast, there is scarce evidence on the role of SUMO conjugation to K721 and its impact on GR transcriptional activity. Our group has previously shown that RSUME (RWD containing SUMOylation Enhancer) increases protein SUMOylation. In the present work, we demonstrate that RSUME interacts with GR and increases its SUMOylation. Moreover, RSUME over-expression enhances GR transcriptional activity in a RWD domain-dependent manner. Most interestingly, RSUME uncovers a positive role for the third SUMOylation site, K721, on GR mediated transcription demonstrating that GR SUMOylation can positively regulate transcription in the presence of a SUMOylation enhancer. Importantly, RSUME, whose expression is induced under stress conditions, is a key factor in heat shock-induced GR SUMOylation. These results highlight the complex relation between SUMO conjugation and GR transcriptional activity and further extend the range of factors capable of fine-tuning the cellular response to glucocorticoids.