Pathogenic roles of immunoproteasomes in fibrosis.

The 26S proteasome is a multi-subunit protease complex that degrades most eukaryotic cellular proteins. It not only regulates individual protein's half-lives but also maintains proteome homeostasis and modulates immunological responses. During conditions involving large-scale proteome remodeling, such as fibrosis and cellular differentiation, the 26S proteasome plays a central role in the rapid removal of excess cytosolic proteins. However, the precise mechanisms underlying this process remain unclear. In this review, we highlight the significance of the immunoproteasome, a specialized variant of the proteasome composed of alternative catalytic subunits, in fibrosis of the kidney, lung, heart, and liver. Immunoproteasomes broaden the antigen repertoire by producing distinct peptide fragments that are preferentially presented to specific immune cell populations. They can also proteolyze substrates with certain ubiquitin (Ub) chain linkages or even those lacking Ub tags. We propose that the immunoproteasome functions as a highly specialized protease in fibrotic tissues, contributing to the transition from a complex but homeostatic proteome to a simple fibrotic proteome.