Abstract
Protein homeostasis (proteostasis) is essential for the cell and is maintained by a highly conserved protein quality control (PQC) system, which triages newly synthesized, mislocalized and misfolded proteins. The ubiquitin-proteasome system (UPS), molecular chaperones, and co-chaperones are vital PQC elements that work together to facilitate degradation of misfolded and toxic protein species through the 26S proteasome. However, the underlying mechanisms are complex and remain partly unclear. Here, we provide an overview of the current knowledge on the co-chaperones that directly take part in targeting and delivery of PQC substrates for degradation. While J-domain proteins (JDPs) target substrates for the heat shock protein 70 (HSP70) chaperones, nucleotide-exchange factors (NEFs) deliver HSP70-bound substrates to the proteasome. So far, three NEFs have been established in proteasomal delivery: HSP110 and the ubiquitin-like (UBL) domain proteins BAG-1 and BAG-6, the latter acting as a chaperone itself and carrying its substrates directly to the proteasome. A better understanding of the individual delivery pathways will improve our ability to regulate the triage, and thus regulate the fate of aberrant proteins involved in cell stress and disease, examples of which are given throughout the review.
Highlights
Protein degradation is a fundamental part of the cellular machinery
We summarize the current knowledge on how misfolded proteins are directed to the proteasome for degradation, and how molecular chaperones and their co-chaperones are involved in this process
Two major elements of the cellular protein quality control (PQC) are the ubiquitin-proteasome system (UPS) and the molecular chaperones and co-chaperones, which collaborate to decide the fate of aberrant protein species
Summary
Protein degradation is a fundamental part of the cellular machinery. An intricate set of protein networks known as the protein quality control (PQC) system coordinates the fate of non-native protein species. In the case of the misfolded protein species that are handled by the PQC system, and likely constantly associate with molecular chaperones, our understanding of proteasomal delivery is more limited. Some misfolded proteins are refractory to degradation and the proteostasis system is known to decline during ageing, giving rise to accumulation of insoluble and aggregation-prone proteins that may be toxic and lead to disease. This has been reviewed in a number of excellent papers [6,7,8] and we will not discuss it further here
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