Catalytically Active Proteasomes Function Predominantly in the Cytosol

The ubiquitin/proteasome pathway is a well characterized system for degrading intracellular proteins, although many aspects remain poorly understood. There is, for instance, a conspicuous lack of understanding of the site(s) where nuclear proteins are degraded because the subcellular distribution of peptidase activity has not been investigated systematically. Although nuclear proteins could be degraded by importing proteasomes into the nucleus, it is also evident that some nuclear proteins are degraded only after export to cytosolic proteasomes. Proteasomes and substrates are mobile, and consequently, the sites of degradation might not be static. We sought to identify the location of proteasomes to provide more conclusive evidence on the sites of protein degradation. We report that catalytically active proteasomes exist almost exclusively in the cytosol. The resulting lack of nuclear peptidase activity suggests that little, if any, degradation occurs in the nucleus. These and other studies suggest that the export of proteolytic substrates could define an important regulatory step in the degradation of nuclear proteins by cytosolic proteasomes.