title: RSUME enhances glucocorticoid receptor SUMOylation and transcriptional activity.
abstract: Glucocorticoid receptor (GR) activity is modulated by posttranslational modifications, including phosphorylation, ubiquitination, and SUMOylation. The GR has three SUMOylation sites: lysine 297 (K297) and K313 in the N-terminal domain (NTD) and K721 within the ligand-binding domain. SUMOylation of the NTD sites mediates the negative effect of the synergy control motifs of GR on promoters with closely spaced GR binding sites. There is scarce evidence on the role of SUMO conjugation to K721 and its impact on GR transcriptional activity. We have previously shown that RSUME (RWD-containing SUMOylation enhancer) increases protein SUMOylation. We now demonstrate that RSUME interacts with the GR and increases its SUMOylation. RSUME regulates GR transcriptional activity and the expression of its endogenous target genes, FKBP51 and S100P. RSUME uncovers a positive role for the third SUMOylation site, K721, on GR-mediated transcription, demonstrating that GR SUMOylation acts positively in the presence of a SUMOylation enhancer. Both mutation of K721 and small interfering RNA-mediated RSUME knockdown diminish GRIP1 coactivator activity. RSUME, whose expression is induced under stress conditions, is a key factor in heat shock-induced GR SUMOylation. These results show that inhibitory and stimulatory SUMO sites are present in the GR and at higher SUMOylation levels the stimulatory one becomes dominant.
authors.affiliation: Instituto de Investigación en Biomedicina de Buenos Aires, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Jimena
authors.initials: J
authors.lastname: Druker
authors.forename: Ana C
authors.initials: AC
authors.lastname: Liberman
authors.forename: María
authors.initials: M
authors.lastname: Antunica-Noguerol
authors.forename: Juan
authors.initials: J
authors.lastname: Gerez
authors.forename: Marcelo
authors.initials: M
authors.lastname: Paez-Pereda
authors.forename: Theo
authors.initials: T
authors.lastname: Rein
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Iñiguez-Lluhí
authors.forename: Florian
authors.initials: F
authors.lastname: Holsboer
authors.forename: Eduardo
authors.initials: E
authors.lastname: Arzt
mesh_terms: D000818:Animals; D001120:Arginine / Q000235:genetics; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002522:Chlorocebus aethiops; D018869:Heat-Shock Response / Q000502:physiology; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000235:genetics* / Q000378:metabolism*; D058207:Sumoylation; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D002352:Carrier Proteins; C491310:GRIP1 protein, human; D009419:Nerve Tissue Proteins; C525338:RWDD3 protein, human; D011965:Receptors, Glucocorticoid; D014157:Transcription Factors; D001120:Arginine