The UBR1 ubiquitin ligase promotes degradation of proteins via the N-end rule and by another mechanism that detects a misfolded conformation. Although UBR1 was shown recently to act on protein kinases whose misfolding was promoted by inhibition of Hsp90, it was unknown whether this ubiquitin ligase targeted other client types of the chaperone. We analyzed the role of UBR1 in the degradation of nuclear receptors that are classical clients of Hsp90. Our results showed that UBR1 deletion results in impaired degradation of the glucocorticoid receptor and the androgen receptor but not the estrogen receptor α. These findings demonstrate specificity in the actions of the UBR1 ubiquitin ligase in the degradation of Hsp90 clients in the presence of small molecule inhibitors that promote client misfolding.
Keywords: AR, androgen receptor; CHIP, C-terminal Hsp interacting protein; DMSO, dimethylsulfoxide; Degradation; ER, estrogen receptor; GA, geldanamycin; GR, glucocorticoid receptor; HA, hemagglutinin; Hsp90; MEF, mouse embryonic fibroblasts; Molecular chaperone; Quality control; UBR1; UPS, ubiquitin proteasome system; Ubiquitin ligase.