Co-Chaperones in Targeting and Delivery of Misfolded Proteins to the 26S Proteasome

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.

Ubiquitin-interacting motifs of ataxin-3 regulate its polyglutamine toxicity through Hsc70-4-dependent aggregation

“…Its closest human ortholog is the constitutively expressed, heat shock protein family A member 8 (HSPA8; Takayama et al, 1999 ). Alongside other HSP70 members, its primary role is that of an ATP-dependent chaperone for unfolded proteins in protein quality control ( Yamamoto et al, 2010 ; Grove et al, 2011 ; Goodwin et al, 2014 ; Li et al, 2017 ; Sopha et al, 2012 ; Robert et al, 2019 ; Loeffler, 2019 ; Abildgaard et al, 2020 ; Davis et al, 2020 ; Faust and Rosenzweig, 2020 ). HSPA8 is a part of the ubiquitin-proteasome degradation system and is also involved in chaperone-mediated autophagy ( Robert et al, 2019 ; Loeffler, 2019 ; Stricher et al, 2013 ; Kampinga and Bergink, 2016 ).…”

HSP70-binding motifs function as protein quality control degrons

“…For Ubr1, a direct interaction with Hsp70 has been observed (Summers et al, 2013), indicating that some PQC E3s may delegate substrate recognition to the chaperones. In the same line, the human CHIP E3 directly interacts with Hsp70 and Hsp90 chaperones to ubiquitylate bound protein substrates (Höhfeld and Jentsch, 1997), while the BAG1 and Hsp110 co-chaperones mediate the release of bound substrates at the 26S proteasome (Abildgaard et al, 2020;Gersing et al, 2021;Höhfeld and Jentsch, 1997;Kandasamy and Andréasson, 2018;Kriegenburg et al, 2014).…”

What's in the BAGs? Intrinsic disorder angle of the multifunctionality of the members of a family of chaperone regulators

“…Despite their sequence differences, all BAG‐1 isoforms contain ubiquitin‐like (UBL) domain (residues 144–224) suggesting involvement of these proteins in the proteasome‐mediated degradation. In fact, BAG‐1 is one of a few NEFs that were shown to deliver HSP70‐bound substrates to the proteasome 105 . On the other hand, some proteins (e.g., tau) can be protected from proteasomal degradation by BAG‐1 106 .…”