Molecular chaperones and the art of recognizing a lost cause

Molecular chaperones have long been heralded as machines for folding and sa lvaging proteins. However, not every attempt to fold or refold a protein ca n be successful. Chaperones are known to participate in the degradation of misfolded polypeptides, but a direct link between folding and degradation p athways 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.