PA28γ: New Insights on an Ancient Proteasome Activator

PA28 (also known as 11S, REG or PSME) is a family of proteasome regulators whose members are widely present in many of the eukaryotic supergroups. In jawed vertebrates they are represented by three paralogs, PA28 alpha, PA28 beta, and PA28 gamma, which assemble as heptameric hetero (PA28 alpha beta) or homo (PA28 gamma) rings on one or both extremities of the 20S proteasome cylindrical structure. While they share high sequence and structural similarities, the three isoforms significantly differ in terms of their biochemical and biological properties. In fact, PA28 alpha and PA28 beta seem to have appeared more recently and to have evolved very rapidly to perform new functions that are specifically aimed at optimizing the process of MHC class I antigen presentation. In line with this, PA28 gamma favors release of peptide products by proteasomes and is particularly suited to support adaptive immune responses without, however, affecting hydrolysis rates of protein substrates. On the contrary, PA28 gamma seems to be a slow-evolving gene that is most similar to the common ancestor of the PA28 activators family, and very likely retains its original functions. Notably, PA28 gamma has a prevalent nuclear localization and is involved in the regulation of several essential cellular processes including cell growth and proliferation, apoptosis, chromatin structure and organization, and response to DNA damage. In striking contrast with the activity of PA28 alpha beta, most of these diverse biological functions of PA28 gamma seem to depend on its ability to markedly enhance degradation rates of regulatory protein by 20S proteasome. The present review will focus on the molecular mechanisms and biochemical properties of PA28 gamma, which are likely to account for its various and complex biological functions and highlight the common features with the PA28 alpha beta paralog.

Automated summary

PA28 is a family of proteasome regulators with three paralogs in jawed vertebrates - PA28 alpha, PA28 beta, and PA28 gamma. PA28 gamma is involved in supporting adaptive immune responses and regulating essential cellular processes in the nucleus. Its ability to enhance degradation rates of regulatory proteins by the 20S proteasome is a key factor in its diverse and complex biological functions.