Keeping proteasomes under control—a role for phosphorylation in the nucleus

Abstract

The 26S proteasome is the primary site for protein breakdown in the nucleus and cytosol of eukaryotic cells. This 60-subunit proteolytic machine selectively degrades ubiquitinated proteins. These substrates initially bind to its 19S regulatory complex, which is located at the ends of the barrel-shaped 20S core proteasome, within which proteins are hydrolyzed to small peptides. This ATP-driven process involves several different enzymatic steps including substrate binding, deubiquitination, unfolding, and translocation into the 20S particle (Fig. 1). However, only recently have clear insights emerged about how these multiple processes are coordinated and how proteasomes become localized to different cellular compartments. For example, recent studies show that binding of ubiquitinated proteins activates the proteasome's degradative machinery (1). Nevertheless, many ubiquitinated proteins bind to the 26S but escape proteolysis, only to be deubiquitinated and released (2). These observations of inherent regulation make it likely that there are also exogenous cellular mechanisms that regulate proteasome activity. Fig. 1. Role of the 26S proteasomes in degrading ubiquitinated proteins. Polyubiquitinated substrates initially bind to subunits Rpn10 and Rpn13 and become deubiquitinated. This process activates proteolysis (24). Substrates are unfolded by the six ATPase subunits (Rpt1–6), which open the gated pore in the α-ring to allow translocation into the 20S core, where they are cleaved to peptides by the six active sites on β-subunits. This illustration is adapted from the EM images provided by Wolfgang Baumeister (Max Planck Institute, Martinsried, Germany) (25). A number of studies have reported that proteasome subunits can be modified by phosphorylation, glycosylation, ubiquitination, or proteolysis by caspases. However, the physiological significance of these posttranslational modifications and their effects on proteasome function has been unclear. Unfortunately, most of these intriguing findings have not yet … [↵][1]2To whom correspondence should be addressed. E-mail: Alfred_Goldberg{at}hms.harvard.edu. [1]: #xref-corresp-1-1