The Nuclear UbiquitinProteasome System: Visualization of Proteasomes, Protein Aggregates, and Proteolysis in the Cell Nucleus

The 20S proteasome is part of a larger complex, the 26S proteasome, that is implicated in the ATP-dependent degradation of multiubiquitin-conjugated proteins (1) . About 80% of intracellular protein breakdown occurs via the ubiquitinproteasome system (UPS). Key proteins such as transcription factors, nuclear receptors, cyclins, cyclin-dependent kinase inhibitors, p53, and NF-κB are regulated by this pathway. Thus, the UPS has been implicated to play a role in multiple cellular events including the cell cycle, signal transduction, antigen presentation, and DNA repair and transcription (2, 3) . In 1984 Varshavsky and co-workers discovered that ubiquitin-dependent pathways play a role in cell cycle control, and suggested that protein degradation is instrumental in regulation of gene expression (4) . Consistent with this idea, Franke and colleagues had shown that proteasomes localize to the nuclei of Xenopus laevis oocytes and HeLa cells (5, 6) . Subsequent work confirmed that (i) all components of the UPS that are required for protein degradation indeed reside in the cell nucleus (7) ; (ii) nuclear proteins are substrates for proteasomal degradation (8) ; and (iii) proteasome-dependent proteolysis occurs in distinct nucleoplasmic foci (9) . The intricate balance between nuclear function and quality control through proteolysis is exemplified by reports that show a correlation of aberrant nuclear protein aggregates with inhibition of transcription in neurodegenerative diseases such as Huntington’s chorea and animal and cell culture models of polyglutamine repeat disorders (10,11) .