Abstract
Molecular chaperones were originally discovered as heat shock-induced proteins that facilitate proper folding of proteins with non-native conformations. While the function of chaperones in protein folding has been well documented over the last four decades, more recent studies have shown that chaperones are also necessary for the clearance of terminally misfolded proteins by the Ub-proteasome system. In this capacity, chaperones protect misfolded degradation substrates from spontaneous aggregation, facilitate their recognition by the Ub ligation machinery and finally shuttle the ubiquitylated substrates to the proteasome. The physiological importance of these functions is manifested by inefficient proteasomal degradation and the accumulation of protein aggregates during ageing or in certain neurodegenerative diseases, when chaperone levels decline. In this review, we focus on the diverse roles of stress-induced chaperones in targeting misfolded proteins to the proteasome and the consequences of their compromised activity. We further discuss the implications of these findings to the identification of new therapeutic targets for the treatment of amyloid diseases.
Highlights
The cell’s capacity to maintain protein homeostasis is constantly challenged, as proteins can often fail to attain or preserve their native conformation due to destabilizing mutations, translation errors, stress conditions or developmental changes [1]
Two functional domains of Bcl2-associated athanogene 1 (BAG-1) act in concert to ensure the proteasomal degradation of CHIP-ubiquitylated substrates: A Ub-like domain (UBL) of BAG-1 that mediates the association with the 26S proteasome [80,81,82] and a conserved BAG domain that mediates Hsp70 binding and triggers the timely substrate release from the Hsp70 complex to the proteasome [83]
We have focused on the multiple roles of Hsp70 chaperones and their co-chaperones, the Hsp40s, as regulators of misfolded protein elimination by the UPS
Summary
The cell’s capacity to maintain protein homeostasis is constantly challenged, as proteins can often fail to attain or preserve their native conformation due to destabilizing mutations, translation errors, stress conditions or developmental changes [1]. A role for molecular chaperones in UPS-mediated degradation was initially proposed by Ciechanover and colleagues who demonstrated that the in vitro ubiquitylation of several proteasome substrates requires the activity of the mammalian heat shock cognate protein 70 (HSC70) [16]. The nature and extent of the association between E3 ligases and the various HSPs is highly specific and the governing rules for their interaction with PQC-dependent substrates are largely unknown [17] In addition to their requirement for substrate recognition, HSPs function downstream to protein-Ub conjugation, as escort factors that deliver and/or dock the Ub-protein conjugates to the proteasome. We provide specific examples to illustrate current models and perceptions and further discuss some of the challenges yet to be solved, in order to better understand the roles and mode of action of chaperones in Ub-mediated proteasomal degradation
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