Immunoproteasomes: Regulating the regulator

If proteins were people, half of the world's population (3 × 10⁹) would cohabit, cheek by jowl, the typically sized vertebrate cell. Proteins are the most abundant macromolecular constituent of cells and certainly the most important and interesting. Because the interactions of proteins with each other and other cellular components are governed by the laws of mass action, the concentration of a protein greatly influences its function. With the ascendance of molecular genetics in the late 1960s, interest in cellular control of the copy number of individual proteins focused nearly exclusively on transcription. But protein expression is determined not only by the rate of synthesis but also by the rate of degradation. Indeed, it was recognized at least five decades ago that nimble control of protein levels can only be achieved by maintaining the capacity for rapid degradation (1). With the awarding of the 2004 Nobel Prize in Chemistry to Ciechanover, Hershko, and Rose for “their discovery of ubiquitin-mediated protein degradation,” protein degradation finally achieved equal footing with transcription in studying protein expression. Ubiquitin covalently marks proteins for degradation by the proteasome, a ubiquitous, abundant, multicatalytic protease that has the unique ability to degrade virtually any protein to oligopeptides. Although much has been learned about the enzymes that control protein ubiquitylation, relatively little is known about how proteasomes themselves are regulated. In this issue of PNAS, Heink et al. (2) report a significant advance in understanding how cells regulate proteasome levels in cells. This finding has broad implications for the possible functions of immunoproteasomes, a form of the proteasome intimately involved with the immune system of jawed vertebrates.

Proteasomes are composed of 14 distinct subunits (seven α and seven β) arrayed in four symmetrical rings (α₇β₇-β₇α₇) to form a barrel with …