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.

The role of protein clearance mechanisms in organismal ageing and age-related diseases

“…Therefore, 20S particles are considered to be inactive, unable to degrade polyubiquitylated proteins 16 . However, free 20S particles have a detectable activity independent of ATP/ubiquitination and could play a significant role in the degradation of oxidized proteins 15,18 . Oxidative modification is a signal for proteolysis by 20S, a process that could gain relevance with age.…”

“…Compared with the 19S, their substrates are less clear although their biological functions are emerging. Blm10/ PA200, a monomeric protein of 250 kDa, forms hybrid complexes in which it binds to one end of the 20S proteasome and the 19S to the opposite end 15 . PA28 is formed by hetero-heptameric rings of 28-kDa proteins (PA28a and PA28b) or homo-heptameric rings of PA28g 16 .…”

“…PA28 is formed by hetero-heptameric rings of 28-kDa proteins (PA28a and PA28b) or homo-heptameric rings of PA28g 16 . PA28ab is inducible by interferon-g and modulates the presentation and generation of specific viral antigens 15 . PA28g is involved in cell cycle regulation promoting the degradation of small proteins such as p21 (ref.…”

“…The UPS is the primary selective proteolytic system in eukaryotic cells 15 , a precise mechanism that maintains the proper concentration of many regulatory proteins involved in multiple biological processes (Fig. 1).…”

“…potential decline during the ageing process and this failure contributes to the development of age-related diseases 11,15 .…”