EFFECTS OF LOVASTATIN ON TRAFFICKING OF CYSTIC-FIBROSIS TRANSMEMBRANECONDUCTANCE REGULATOR IN HUMAN TRACHEAL EPITHELIUM

Genetic defects in the cystic fibrosis transmembrane conductance regul ator (CFTR), a cAMP-activated chloride channel, cause cystic fibrosis. Most defective forms of CFTR show improper intracellular trafficking. Because isoprenylated, small GTP-binding proteins are involved in the vesicular trafficking of other integral membrane proteins, we have in vestigated the role of isoprenylation in the trafficking of CFTR to th e apical membranes of primary cultures of human airway epithelium and of Calu-3 cells, a human lung carcinoma cell line, CFTR function was m easured as short circuit current, I-125 efflux, and conductance of cel l sheets with permeabilized basolateral membranes. Lovastatin, an inhi bitor of isoprenyl lipid biosynthesis, markedly inhibited all measures of CFTR function, The lovastatin-induced declines in CFTR function we re corrected by the simultaneous addition of mevalonate or the isopren yl Lipids geranylgeranyl and farnesyl but not cholesterol. Lovastatin reduced total cellular CFTR as assessed by immunoprecipitation. Mevalo nate or isoprenyl lipids protected CFTR levels from the actions of lov astatin. Together, these results suggest a role for isoprenyl lipids, presumably through the actions of small GTP-binding proteins, in the t rafficking of CFTR to the apical membrane of human airway epithelium.