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.
Highlights
Alois Alzheimer’s discovery in 1906 of senile plaques in histological brain sections [1] attracted little attention from the scientific community [2]
We shall discuss the turnover of dynamic protein inclusions, the manner of their dissolution, focusing on the role of the ubiquitin-proteasome system (UPS) in this process
Hsp104 activity is required for the turnover of aggregation-prone, membrane-embedded, Endoplasmic Reticulum-Associated Degradation (ERAD) substrates, but not for their soluble counterparts [36]. These findings indicate that yeast Hsp104 is capable of contributing an extraction force for both the refolding of proteins that emerge from trans-Q and the retro-translocation of ERAD substrates across the ER membrane
Summary
Alois Alzheimer’s discovery in 1906 of senile plaques in histological brain sections [1] attracted little attention from the scientific community [2]. Overwhelming of the chaperone system is likely a trigger for misfolded protein deposition when Hsp70-dependent delivery of ubiquitylated proteins to the proteasome is inhibited, leading to their sequestration [22,23] It is still unclear how the relief of proteotoxic stress triggers aggregate clearance and how the ensuing fate of disaggregated proteins to either refolding or proteasomal degradation is determined. The term “triage” in PQC was initially coined by Gottesman, Wickner, and Muarizi, referring to a bacterial chaperone mechanism that discerns the folding state of proteins and subsequently targets misfolded proteins to degradation [24] It is most likely a selective process whereupon initially, individual proteins are extracted and solubilized, after which their folding state is discerned and refolding or disposal is determined. It was only when the dynamics of pre-formed protein inclusions in yeast had been investigated under conditions where new protein synthesis is curtailed, that a key role of proteasomes in transient-QC clearance was realized [8,32,38]
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