Releasing the Lockdown: An Emerging Role for the Ubiquitin-Proteasome System in the Breakdown of Transient Protein Inclusions

Abstract

Intracellular protein inclusions are diverse cellular entities with distinct biological properties. They vary in their protein content, sequestration sites, physiological function, conditions for their generation, and turnover rates. Major distinctions have been recognized between stationary amyloids and dynamic, misfolded protein deposits. The former being a dead end for irreversibly misfolded proteins, hence, cleared predominantly by autophagy, while the latter consists of a protein-quality control mechanism, important for cell endurance, where proteins are sequestered during proteotoxic stress and resolved upon its relief. Accordingly, the disaggregation of transient inclusions is a regulated process consisting of protein solubilization, followed by a triage step to either refolding or to ubiquitin-mediated degradation. Recent studies have demonstrated an indispensable role in disaggregation for components of the chaperone and the ubiquitin–proteasome systems. These include heat-shock chaperones of the 40/70/100 kDa families, the proteasome, proteasome substrate shuttling factors, and deubiquitylating enzymes. Thus, a functional link has been established between the chaperone machinery that extracts proteins from transient deposits and 26S proteasome-dependent disaggregation, indicative of a coordinated process. In this review, we discuss data emanating from these important studies and subsequently consolidate the information in the form of a working model for the disaggregation mechanism.

Ubiquitination-Proteasome System (UPS) and Autophagy Two Main Protein Degradation Machineries in Response to Cell Stress

“…Ubiquitin is a classical molecular label for protein degradation. When the misfolded proteins and unfolded proteins are tagged with ubiquitin, these proteins will be degraded in proteasome or lysosome [ 8 , 9 ]. Ubiquitin not only plays a role in UPR, but also participates in the activation of cellular stress responses.…”

Age-dependent aggregation of ribosomal RNA-binding proteins links deterioration in chromatin stability with challenges to proteostasis

“…In contrast, deletion of UBR2 , which encodes a ubiquitin ligase that mediates Rpn4 degradation, leads to elevated proteasome capacity ( Wang et al, 2004 ) and thereby dramatically alleviated Nop15 aggregation ( Figure 4B , right). These results suggest that the proteasome participates in the process of removing age-induced rRNA-binding protein aggregates, probably through degradation of intrinsically disordered protein monomers as in the case of other misfolded protein aggregates or aberrant RNA-binding protein aggregates ( Berke and Paulson, 2003 ; Brown and Kaganovich, 2016 ; Hjerpe et al, 2016 ; Reiss et al, 2020 ; Thapa et al, 2020 ).…”

Age-dependent aggregation of ribosomal RNA-binding proteins links deterioration in chromatin stability with loss of proteostasis

“…4B, right). These results suggest that the proteasome participates in the process of removing age-induced rRNA-binding protein aggregates, probably through degradation of intrinsically disordered protein monomers as in the case of other misfolded protein aggregates or aberrant RNA-binding protein aggregates (Berke and Paulson, 2003;Brown and Kaganovich, 2016;Hjerpe et al, 2016;Reiss et al, 2020;Thapa et al, 2020).…”