Regulation of glucocorticoid receptor activity by cellular stress
Laura Davies, Malihah Sadeq, Constantinos Demonacos & Marija Krstic-Demonacos
Cofactors of the nuclear hormone receptors are crucial in regulating their transcriptional activity. The glucocorticoid receptor (GR) is a member of the nuclear hormone receptor superfamily, involved in the regulation of metabolism, inflammation and stressresponses and many GR cofactors are known, including p300. Here, we identify a new cofactor for GR: TTC5/Strap, tetratricopeptide repeat domain 5/ stressresponsive activator of p300. Strap is a TPR motif containing protein, which forms a complex with p300 histone acetyl transferase. This complex regulates p53 in response to DNA damage. Given the role of TPR motif containing proteins as co-chaperones of nuclear receptors, here we investigate the effects of TTC5 on GR function. We have shown that GR and Strap interact through multiple binding motifs and that this interaction is modulated by cellular stress such as DNA damage and heat shock. TTC5 stabilises GR and regulate the transcriptional activity of GR, in a target gene specific manner. TTC5 also plays a role in the regulation of oestrogen receptor. In conclusion, our results suggest an important role for TTC5 in the regulation of nuclear hormone receptor function in response to cellular stress.