DEFECTIVE ACIDIFICATION OF INTRACELLULAR ORGANELLES IN CYSTIC-FIBROSIS

THE phenotype of cystic fibrosis (CF) includes abnormalities in transepithelial transport of Cl- (refs 1-5), decreased sialylation and increased sulphation and fucosylation of glycoproteins 6-9, and lung colonization with Pseudomonas. It is not apparent how these abnormalities are interrelated, nor how they result from loss of function of the CF gene-encoded transmembrane regulator (CFTR) 10. We have previously shown that that the pH of a secretory granule is regulated by the vesicular conductance for Cl- (ref. 11). Here we find defective acidification in CF cells of the trans-Golgi/trans-Golgi network, of prelysosomes and of endosomes as a result of diminished Cl- conductance. Sialylation of proteins and lipids is reduced and ligand traffic altered. These abnormalities can result from defective acidification because vacuolar pH regulates glycoprotein processing and ligand transport. The CF phenotype is similar to that of alkalinized cells 12 and acidification-defective mutatants 13.