Perturbation of Hsp90 interaction with nascent CFTR prevents its maturation and accelerates its degradation by the proteasome

Maturation of wild-type CFTR nascent chains at the endoplasmic reticulum (E R) occurs inefficiently; many disease-associated mutant forms do not mature but instead are eliminated by proteolysis involving the cytosolic proteaso me, Although calnexin binds nascent CFTR via its oligosaccharide chains in the ER lumen and Hsp70 binds CFTR cytoplasmic domains, perturbation of thes e interactions alone is without major influence on maturation or degradatio n. We show that the ansamysin drugs, geldanamycin and herbimycin A, which i nhibit the assembly of some signaling molecules by binding to specific site s on Hsp90 in the cytosol or Grp94 in the ER lumen, block the maturation of nascent CFTR and accelerate its degradation, The immature CFTR molecule wa s detected in association with Hsp90 but not with Grp94, and geldanamycin p revented the Hsp90 association. The drug-enhanced degradation was decreased by lactacystin and other proteasome inhibitors. Therefore, consistent with other examples of countervailing effects of Hsp90 and the proteasome, it w ould seem that this chaperone may normally contribute to CFTR folding and, when this function is interfered with by an ansamycin, there is a further s hift to proteolytic degradation. This is the first direct evidence of a rol e for Hsp90 in the maturation of a newly synthesized integral membrane prot ein by interaction with its cytoplasmic domains on the ER surface.