A truncated CFTR protein rescues endogenous Delta F508-CFTR and corrects chloride transport in mice

Article

关键词: TRANSMEMBRANE CONDUCTANCE REGULATOR;    CYSTIC-FIBROSIS MUTATION;    ENDOPLASMIC-RETICULUM;    EPITHELIAL-CELLS;    AIRWAY EPITHELIA;    PLASMA-MEMBRANE;    LOW-TEMPERATURE;    GENE-THERAPY;    CHANNELS;    PROTEASOME;   

DOI  :  10.1096/fj.08-127878

来源: SCIE

【 摘 要 】

Cystic fibrosis (CF) is most frequently associated with deletion of phenylalanine at position 508 (Delta F508) in the CF transmembrane conductance regulator (CFTR) protein. The Delta F508-CFTR mutant protein exhibits a folding defect that affects its processing and impairs chloride-channel function. This study aimed to determine whether CFTR fragments approximately half the size of wild-type CFTR and complementary to the portion of CFTR bearing the mutation can specifically rescue the processing of endogenous Delta F508-CFTR in vivo. cDNA encoding CFTR fragments were delivered to human airway epithelial cells and mice harboring endogenous Delta F508-CFTR. Delivery of small CFTR fragments, which do not act as chloride channels by themselves, rescue Delta F508-CFTR. Therefore, we can speculate that the presence of the CFTR fragment, which does not harbor a mutation, might facilitate intermolecular interactions. The rescue of CFTR was evident by the restoration of chloride transport in human CFBE41o- bronchial epithelial cells expressing Delta F508-CFTR in vitro. More important, nasal administration of an adenovirus expressing a complementary CFTR fragment restored some degree of CFTR activity in the nasal airways of Delta F508 homozygous mice in vivo. These findings identify complementary protein fragments as a viable in vivo approach for correcting disease-causing misfolding of plasma membrane proteins.-Cormet-Boyaka, E., Hong, J. S., Berdiev, B. K., Fortenberry, J. A., Rennolds, J., Clancy, J. P., Benos, D. J., Boyaka, P. N., Sorscher, E. J. A truncated CFTR protein rescues endogenous Delta F508-CFTR and corrects chloride transport in mice. FASEB J. 23, 3743-3751 (2009). www.fasebj.org

【 授权许可】

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