Cellular Handling of Protein Aggregates by Disaggregation Machines

• Published in: Molecular cell Vol. 69; no. 2; pp. 214 - 226
• Main Authors: Mogk, Axel, Bukau, Bernd, Kampinga, Harm H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18.01.2018
• Subjects: chaperones; Cytosol - metabolism; disaggregase; DNAJ proteins; Heat-Shock Proteins - metabolism; Hsp100; HSP110 Heat-Shock Proteins - metabolism; Hsp70; HSP70 Heat-Shock Proteins - metabolism; HSP70 Heat-Shock Proteins - physiology; Molecular Chaperones - metabolism; Protein Aggregates - physiology; protein aggregation; Protein Binding; protein conformation diseases; Protein Folding; Protein Unfolding; Proteolysis; sHsp; thermotolerance; Hsp70; disaggregase; DNAJ proteins; thermotolerance; protein aggregation; protein conformation diseases; sHsp; Hsp100; chaperones
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2018.01.004

Both acute proteotoxic stresses that unfold proteins and expression of disease-causing mutant proteins that expose aggregation-prone regions can promote protein aggregation. Protein aggregates can interfere with cellular processes and deplete factors crucial for protein homeostasis. To cope with these challenges, cells are equipped with diverse folding and degradation activities to rescue or eliminate aggregated proteins. Here, we review the different chaperone disaggregation machines and their mechanisms of action. In all these machines, the coating of protein aggregates by Hsp70 chaperones represents the conserved, initializing step. In bacteria, fungi, and plants, Hsp70 recruits and activates Hsp100 disaggregases to extract aggregated proteins. In the cytosol of metazoa, Hsp70 is empowered by a specific cast of J-protein and Hsp110 co-chaperones allowing for standalone disaggregation activity. Both types of disaggregation machines are supported by small Hsps that sequester misfolded proteins. In this issue of Molecular Cell, Mogk et al. provide a review on the mechanism of action of the different protein disaggregation machines in metazoan and non-metazoan and their potential importance for resistance to acute and chronic proteotoxic stress.