Hsp90: Bringing it all together

Heat-shock protein 90 (Hsp90) is an ancient and multifaceted protein-folding machine essential for most organisms. The past 40 years have uncovered remarkable complexity in the regulation and function of Hsp90, which dwarfs most other machines in the cell in sophistication. Here, we propose four analogies to illustrate Hsp90's sophistication: a multifunctional Swiss Army knife, an automobile engine and its controls, a switchboard acting as a hub and directing signals, and an orchestra conductor setting the tempo of a symphony. Although each of these analogies represents some key Hsp90 activities, none of them captures the entirety of Hsp90's complexity. Together, these roles enable Hsp90 to support both homeostasis and differentiation, both cellular stability and adaptability. At the 11th International Conference on the Hsp90 Chaperone Machine, the consensus was that to understand this major guardian of proteostasis, we need to study how the many facets of Hsp90's function influence each other. We hope that these analogies will help to conceptually integrate the many roles of Hsp90 in proteostasis and help the field develop the practical applications of Hsp90 modulators.