Molecular chaperones and the art of recognizing a lost cause

Molecular chaperones have long been heralded as machines for folding and salvaging proteins. However, not every attempt to fold or refold a protein can be successful. Chaperones are known to participate in the degradation of misfolded polypeptides, but a direct link between folding and degradation pathways has remained elusive. Two recent reports show that the co-chaperone CHIP mediates ubiquitin-dependent degradation of substrates bound to heat-shock protein 70 (Hsp70) and/or Hsp90.