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

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.