PA28 associates and reduce constitutive proteasomes activity to promote immunoproteasome function

Protein homeostasis is a fundamental requirement from all living organisms to sustain viability in an ever-changing environment. One of the key components in maintaining protein homeostasis is the 26S proteasome that is composed of a catalytic particle (20S) and a regulatory particle (19S). In addition to the 26S core particle, several alternative regulatory complexes have been identified and presumed to regulate 20S proteasomal activity under specific conditions. One such particle is the PA28ab heptameric ring that is transcriptionally induced by interferon γ (IFN- γ), along side with unique catalytic subunits of the immunoproteasome. The central role of the ubiquitin-proteasome system in antigen presentation together with the above findings placed the PA28 particle as a bona-fide component of the immunoproteasome.

We present new data showing that PA28 association with the proteasome is regulated by specific stress conditions, that do not necessarily induce the expression of the immunoproteasome catalytic subunits. Furthermore, even under IFN- γ stimulation, the immunoproteasome is found to be mutually exclusive from the PA28-constitutive proteasome particle. We demonstrate the influence of PA28 on 20S catalytic accessibility and postulate the role of PA28ab on antigenic cross-presentation.

We propose a novel mechanism for protein degradation in oxidative stress and immune challenge, suggesting PA28 plays a role in shifting the flux of protein degradation in the cell towards autophagy or to the immunoproteasome, to tackle proteotoxic effects of oxidized proteins.