See related articles, pages 362–371 and 372–380 The ubiquitin–proteasome system (UPS) is the main pathway for the nonlysosomal degradation of intracellular proteins, representing upwards of 80% of all intracellular proteins. A key component of the UPS is the 26S proteasome, a macromolecular multisubunit complex that has the responsibility of recognizing, unfolding, and the ultimately destroying proteins that have been tagged by polyubiquitin chains generally at the e-NH2 group of an internal substrate lysine residue. This is a multistep process that has been reviewed in detail elsewhere.1,2 What has become clear is that the rapid destruction of these proteins, some with high biological activity, actually represents a form of regulation of cellular processes. The UPS is now recognized as a regulator of the cell cycle and cell division,3 immune response and antigen presentation,4 apoptosis,5 and cell signaling.6,7 Moreover, the UPS plays critical roles in protein quality by removal of damaged, oxidized, and/or misfolded proteins.8,9 Ciechanover et al10 have aptly referred to this process as “biological regulation via destruction.” Over the past few years, it has become increasingly clear that this critical regulatory system becomes dysfunctional in certain disease states, such as Alzheimer’s disease, Huntingdon’s disease, and amyotrophic lateral sclerosis.11 With respect to the cardiovascular system, recent studies have suggested that myocardial ischemia,12,13 certain mutant protein–associated cardiomyopathies,14 atherosclerosis,15 and even diabetes16 may be examples of proteasomal dysfunction disorders. Despite all of the evidence supporting the critical role that the UPS plays in these processes, little is know about how the 26S proteasome itself is regulated. The majority of studies have focused on substrate specificity and selectivity, function of the ubiquitin protein ligases or E3s, as a means of regulating activity of the UPS. Specificity can be accounted for …