Hsp70 molecular chaperone facilitates endoplasmic reticulum-associated protein degradation of cystic fibrosis transmembrane conductance regulator in yeast

Membrane and secretory proteins fold in the endoplasmic reticulum (ER), and misfolded proteins may be retained and targeted for ER-associated protein degradation (ERAD). To elucidate the mechanism by which an integral membran e protein in the ER is degraded, we studied the fate of the cystic fibrosis transmembrane conductance regulator (CFTR) in the yeast Saccharomyces cere visiae. Our data indicate that CFTR resides in the ER and is stabilized in strains defective for proteasome activity or deleted for the ubiquitin-conj ugating enzymes Ubc6p and Ubc7p, thus demonstrating that CFTR is a bona fid e ERAD substrate in yeast. We also found that heat shock protein 70 (Hsp70) , although not required for the degradation of soluble lumenal ERAD substra tes, is required to facilitate CFTR turnover. Conversely, calnexin and bind ing protein (BiP), which are required for the proteolysis of ER lumenal pro teins in both yeast and mammals, are dispensable for the degradation of CFT R, suggesting unique mechanisms for the disposal of at least some soluble a nd integral membrane ERAD substrates in yeast.