The Contribution of the 20S Proteasome to Proteostasis

Abstract

The last decade has seen accumulating evidence of various proteins being degraded by the core 20S proteasome, without its regulatory particle(s). Here, we will describe recent advances in our knowledge of the functional aspects of the 20S proteasome, exploring several different systems and processes. These include neuronal communication, post-translational processing, oxidative stress, intrinsically disordered protein regulation, and extracellular proteasomes. Taken together, these findings suggest that the 20S proteasome, like the well-studied 26S proteasome, is involved in multiple biological processes. Clarifying our understanding of its workings calls for a transformation in our perception of 20S proteasome-mediated degradation-no longer as a passive and marginal path, but rather as an independent, coordinated biological process. Nevertheless, in spite of impressive progress made thus far, the field still lags far behind the front lines of 26S proteasome research. Therefore, we also touch on the gaps in our knowledge of the 20S proteasome that remain to be bridged in the future.

Keywords: 20S proteasome; cellular homeostasis; intrinsically disordered proteins; neuronal communication; oxidative stress; protein degradation.

Figure 1

A scheme summarizing the various biological systems and pathways influenced by 20S proteasome activity. Multiple cellular processes are influenced by the 20S proteasome, such as the degradation of intrinsically disordered proteins (IDPs), the oxidative stress response during which the 19S regulatory particle dissociates from the 20S proteasome while leaving 20S proteasome activity intact, and the production of peptides at the neuronal membrane to facilitate neuronal communication. In addition, the 20S proteasome post-translationally processes certain proteins, leading to products with altered functionality compared with the parent protein. Furthermore, the discovery of 20S proteasomes in the extracellular space, both free circulating 20S proteasomes and those found within extracellular vesicles, indicate an involvement in a broad range of biological pathways beyond the confines of the cell.

Figure 2

There are many unknown elements in the 20S proteasome degradation pathway. The scheme summarizes the different substrate groups, 20S proteasome forms, activators, inhibitors, and shuttle proteins, and point toward the many entities among these players that are yet to be discovered. HSP70: heat shock protein 70, IDR: intrinsically disordered proteins, PTM: post translational modification.