Regulation of proteasome activity in health and disease

Abstract

The ubiquitin-proteasome system (UPS) is the primary selective degradation system in the nuclei and cytoplasm of eukaryotic cells, required for the turnover of myriad soluble proteins. The hundreds of factors that comprise the UPS include an enzymatic cascade that tags proteins for degradation via the covalent attachment of a poly-ubiquitin chain, and a large multimeric enzyme that degrades ubiquitinated proteins, the proteasome. Protein degradation by the UPS regulates many pathways and is a crucial component of the cellular proteostasis network. Dysfunction of the ubiquitination machinery or the proteolytic activity of the proteasome is associated with numerous human diseases. In this review we discuss the contributions of the proteasome to human pathology, describe mechanisms that regulate the proteolytic capacity of the proteasome, and discuss strategies to modulate proteasome function as a therapeutic approach to ameliorate diseases associated with altered UPS function. This article is part of a Special Issue entitled: Ubiquitin-Proteasome System. Guest Editors: Thomas Sommer and Dieter H. Wolf.

Keywords: Proteasome; Protein degradation; Ubiquitin.

Figure 1. Modular structure of proteasome complexes

The proteasome core particle can be capped with three different activator complexes: the hetero-oligomeric RP/19S/PA700 particle, the monomeric Blm10/PA200 proteins and the heptameric PA28/11S/REG rings (adapted from 11 and 9). Activators from all three families occupy the same binding site at the apical surface of the CP and open the CP gate.

Figure 2. Model for feedback regulation of proteasomal gene transcription

A) Under normal growth conditions proteasomes are expressed at basal levels. Elevated expression of proteasomal genes is prevented via rapid ubiquitin-dependent degradation of a transcription factor that recognizes specific motifs in the promoter of proteasome genes: PACE and ARE elements in yeast and mammalian cells, respectively. B) Proteotoxic stress (indicated by accumulating damaged proteins symbolized as stars) saturates existing proteasome complexes, resulting in stabilization of the transcription factor and subsequent increased expression of proteasomal genes.