Mechanisms Regulating the UPS-ALS Crosstalk: The Role of Proteaphagy

Abstract

Protein degradation is tightly regulated inside cells because of its utmost importance for protein homeostasis (proteostasis). The two major intracellular proteolytic pathways are the ubiquitin-proteasome and the autophagy-lysosome systems which ensure the fate of proteins when modified by various members of the ubiquitin family. These pathways are tightly interconnected by receptors and cofactors that recognize distinct chain architectures to connect with either the proteasome or autophagy under distinct physiologic and pathologic situations. The degradation of proteasome by autophagy, known as proteaphagy, plays an important role in this crosstalk since it favours the activity of autophagy in the absence of fully active proteasomes. Recently described in several biological models, proteaphagy appears to help the cell to survive when proteostasis is broken by the absence of nutrients or the excess of proteins accumulated under various stress conditions. Emerging evidence indicates that proteaphagy could be permanently activated in some types of cancer or when chemoresistance is observed in patients.

Keywords: autophagy; pathology; proteaphagy; ubiquitin proteasome system; ubiquitin-like.

Figure 1

Proteasome complexity. The 26S proteasome is the most studied proteasome. However, alternative regulatory particles 19S, PA28 or PA200 are able to cap the core 20S proteasome to modulate its proteolytic activity. All these proteasome complexes (20S, 26S, 30S or hybrids) have been found in cells.

Figure 2

Selective autophagy pathways ensure the degradation of specific cargoes but also bulk of proteins. A complex signaling pathway regulates autophagy and induces the lipidation of ATG8 proteins within the newly formed cup shaped membrane, called phagophore. Recruitment of the autophagy substrate marks the maturation of the autophagosome. The substrate tethering to lipidated ATG8 is ensured by autophagy receptors (R). Autophagosomes then fuse with lysosomes, forming autolysosomes in which trapped substrates are degraded.

Figure 3

Main steps occurring during proteaphagy. In mammalian cells, ubiquitylated proteasomes are recognized by the autophagy receptor p62 that interacts with lipidated ATG8 proteins tethered into the autophagosome membranes. The late fusion with lysosome ensures the enzymatic degradation of captured proteasomes.