Emerging roles of the ubiquitin proteasome system in nuclear hormone receptor signaling.

Nuclear receptor (NR)-mediated transcription is intimately tied to the ubiquitin proteasome system (UPS). The UPS targets numerous NR and coregulator proteins, regulating their stability and altering their transcriptional activities through the posttranslational placement of ubiquitin marks on them. Differences in the manner in which ubiquitin is attached to target proteins or itself have distinct regulatory consequences. Protein monoubiquitination, polyubiquitination, the site of ubiquitin attachment to a target protein, and the type of polyubiquitin chain linkage all lead to different biological outcomes and have an important regulatory function in NR-mediated transcription. Consistent with its role in protein degradation, the UPS is able to limit the biological actions of both NRs and coregulators by reducing their protein concentrations in the cell. However, in spite of its destructive capabilities, the UPS can play a positive role in facilitating NR-mediated transcription as well. In addition, ubiquitin-like modifications such as SUMOylation also modify and regulate NRs and coregulators. The UPS forms a key biological system that underlies a sophisticated postranslational regulatory scheme from which complex and dynamic regulation of NR-mediated transcription can occur.