To be, or not to be — molecular chaperones in protein degradation

Abstract

To be, or not to be--that is the question not only for Hamlet in Shakespeare's drama but also for a protein associated with molecular chaperones. While long viewed exclusively as cellular folding factors, molecular chaperones recently emerged as active participants in protein degradation. This places chaperones at the center of a life or death decision during protein triage. Here we highlight molecular mechanisms that underlie chaperone action at the folding/degradation interface in mammalian cells. We discuss the importance of chaperone-assisted degradation for the regulation of cellular processes and its emerging role as a target for therapeutic intervention in cancer and amyloid diseases.

Firefly luciferase mutants as sensors of proteome stress

“…While macroautophagy and microautophagy are non-selective for their targets, chaperone mediated autophagy (CMA) (Cuervo, 2011) and chaperone-assisted selective autophagy (CASA) (Arndt et al, 2007;Kettern et al, 2010) are highly selective forms of autophagy. Macroautophagy is a process where cellular organelles like mitochondria (mitophagy), giant proteins like ribosomes (ribophagy), lipid droplets (lipophagy) and protein aggregates are secluded 'in bulk' from the cytosol by a de novo formed double membrane vesicle called autophagosome (Mizushima et al, 2002).…”

“…Unlike CMA, which does not involve vesicle formation or invagination, CASA involves selective engulfment of the substrates by an autophagic isolated membrane leading to lysosomal degradation (Arndt et al, 2007;Kettern et al, 2010). In CASA, ubiquitination serves as an initial degradation signal, comparable to the proteasomal degradation.…”

“…This is achieved by refolding and/or degradation pathways that have been shown to integrate with each other to remove these misfolded proteins (Arndt et al, 2007). In cells, refolding is thermodynamically favorable over protein degradation and the decision between these two pathways may depend on two factors.…”

“…In cells, refolding is thermodynamically favorable over protein degradation and the decision between these two pathways may depend on two factors. First, the recognition of damage through specific features of the substrate and second, if chaperone mediated refolding fails, the substrate is directed to the degradation pathway (Arndt et al, 2007;Kettern et al, 2010). This means that surface features on a substrate protein, most likely exposed hydrophobic residues, determine the decision of cells whether to refold or degrade a substrate.…”

Chaperone-assisted degradation: multiple paths to destruction

“…Over the past decade it has become increasingly clear, however, that many chaperones, including members of the Hsp70 and Hsp90 chaperone families and small heat shock proteins, participate very actively in protein degradation. By interacting with components of the degradation systems, these chaperones were shown to facilitate the disposal of non-native proteins through proteasomal and autophagic degradation Arndt et al, 2007Arndt et al, , 2010Carra et al, 2008;Gamerdinger et al, 2009).…”