MULTIPLE PROTEOLYTIC SYSTEMS, INCLUDING THE PROTEASOME, CONTRIBUTE TOCFTR PROCESSING

The molecular components of the quality control system that rapid ly d egrades abnormal membrane and secretory proteins have not been identif ied. The cystic fibrosis transmembrane conductance regulator (CFTR) is an integral membrane protein to which this quality control is stringe ntly applied; similar to 75% of the wild-type precursor and 100% of th e Delta F508 CFTR variant found in most CF patients are rapid ly degra ded before exiting from the ER. We now show that this ER degradation i s sensitive to inhibitors of the cytosolic proteasome, including lacta cystin and certain peptide aldehydes. One of the latter compounds, MG- 132, also completely blocks the ATP-dependent conversion of the wild-t ype precursor to the native folded form that enables escape from degra dation. Hence, CFTR and presumably other intrinsic membrane proteins a re substrates for proteasomal degradation during their maturation with in the ER.