Regulation of the 26S Proteasome: From Homeostasis to Stress and Disease

The ubiquitin–proteasome system (UPS) has traditionally been described as a tightly regulated degradative network driven mainly by the specificity of its ubiquitin-conjugating enzymatic components. The 26S proteasome is the catalytic arm of the system that acts downstream to the conjugation machinery. For a long time, it has been considered to be a constitutive multi-subunit proteolytic complex that recognizes in a non-discriminatory manner ubiquitin-marked target substrates with less than a handful of exceptions. However, emerging evidence reveals that the 26S proteasome function is also dynamically regulated by multiple factors, such as subunit composition and synthesis, post-translational modifications, and spatial localization, all of which are tightly regulated by the metabolic and stress states of the cell. Importantly, dysregulation of these newly emerging regulatory mechanisms has pathogenic sequelae. These mechanisms fine-tune proteasome activity and expand its role as an active regulator of protein homeostasis rather than being a passive degradation machinery. Given the rapid expansion of these findings and their impact on our understanding of proteasome biology, an integrated overview of these regulatory mechanisms is timely.