Processing of mutant cystic fibrosis transmembrane conductance regulator is temperature-sensitive

• Published in: Nature (London) 1992-08, Vol.358 (6389), p.761-764
• Main Authors: Denning, Gerene M, Anderson, Matthew P, Amara, Jane F, Marshall, John, Smith, Alan E, Welsh, Michael J
• Format: Article
• Language: English
• Subjects: 3T3 Cells; Animals; Biochemistry; Biological and medical sciences; Cell Compartmentation; Cell Membrane - metabolism; channels; chloride; Chloride Channels; Cold Temperature; Cystic fibrosis; Cystic Fibrosis - metabolism; Cystic Fibrosis Transmembrane Conductance Regulator; epithelium; Gastroenterology. Liver. Pancreas. Abdomen; Glycosylation; Humanities and Social Sciences; Humans; In Vitro Techniques; letter; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Low temperature; man; Medical research; Medical sciences; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Membrane Proteins - metabolism; Membranes; Mice; multidisciplinary; mutants; Mutation; Other diseases. Semiology; processing; Protein Processing, Post-Translational; Science; Science (multidisciplinary); sensitive; Temperature; transmembrane conductance regulator
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/358761a0

CYSTIC fibrosis transmembrane conductance regulator (CFTR) is a plasma membrane Cl − channel regulated by cyclic AMP-dependent phosphorylation and by intracellular ATP 1–7 . Mutations in CFTR cause cystic fibrosis 8–10 partly through loss of cAMP-regulated Cl − permeability from the plasma membrane of affected epithelia 11,12 . The most common mutation in cystic fibrosis is deletion of phenylalanine at residue 508 (CFTRΔF508) (ref. 10). Studies on the biosynthesis 13,14 and localization 15 of CFTRΔF508 indicate that the mutant protein is not processed correctly and, as a result, is not delivered to the plasma membrane. These conclusions are consistent with earlier functional studies which failed to detect cAMP-stimnlated Cl − channels in cells expressing CFTRΔF508 (refs 16,17). Chloride channel activity was detected, however, when CFTRΔF508 was expressed in Xenopus oocytes 18 , Vero cells 19 and Sf9 insect cells 20 . Because oocytes and Sf9 cells are typically maintained at lower temperatures than mammalian cells, and because processing of nascent proteins can be sensitive to temperature 21 , we tested the effect of temperature on the processing of CFTRΔF508. Here we show that the processing of CFTRΔF508 reverts towards that of wild-type as the incubation temperature is reduced. When the processing defect is corrected, cAMP-regulated Cl − channels appear in the plasma membrane. These results reconcile previous contradictory observations and suggest that the mutant most commonly associated with cystic fibrosis is temperature-sensitive.