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 membrane 
protein in the ER is degraded, we studied the fate of the cystic fibrosis 
transmembrane conductance regulator (CFTR) in the yeast Saccharomyces 
cerevisiae. Our data indicate that CFTR resides in the ER and is stabilized in 
strains defective for proteasome activity or deleted for the 
ubiquitin-conjugating enzymes Ubc6p and Ubc7p, thus demonstrating that CFTR is a 
bona fide ERAD substrate in yeast. We also found that heat shock protein 70 
(Hsp70), although not required for the degradation of soluble lumenal ERAD 
substrates, is required to facilitate CFTR turnover. Conversely, calnexin and 
binding protein (BiP), which are required for the proteolysis of ER lumenal 
proteins in both yeast and mammals, are dispensable for the degradation of CFTR, 
suggesting unique mechanisms for the disposal of at least some soluble and 
integral membrane ERAD substrates in yeast.