Abstract
Cystic fibrosis (CF) is most frequently associated with deletion of phenylalanine at position 508 (ΔF508) in the CF transmembrane conductance regulator (CFTR) protein. The ΔF508-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 ΔF508-CFTR in vivo. cDNA encoding CFTR fragments were delivered to human airway epithelial cells and mice harboring endogenous ΔF508-CFTR. Delivery of small CFTR fragments, which do not act as chloride channels by themselves, rescue ΔF508-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 ΔF508-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 ΔF508 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.
| Original language | English |
|---|---|
| Pages (from-to) | 3743-3751 |
| Number of pages | 9 |
| Journal | FASEB Journal |
| Volume | 23 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - 2009 |
| Externally published | Yes |
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Keywords
- Cystic fibrosis
- In vivo rescue
- Processing
- Transcomplementation
ASJC Scopus subject areas
- Biochemistry
- Biotechnology
- Genetics
- Molecular Biology
Cite this
A truncated CFTR protein rescues endogenous ΔF508-CFTR and corrects chloride transport in mice. / Cormet-Boyaka, Estelle; Hong, Jeong S.; Berdiev, Bakhram K.; Fortenberry, James A.; Rennolds, Jessica; Clancy, J. P.; Benos, Dale J.; Boyaka, Prosper N.; Sorscher, Eric J.
In: FASEB Journal, Vol. 23, No. 11, 2009, p. 3743-3751.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - A truncated CFTR protein rescues endogenous ΔF508-CFTR and corrects chloride transport in mice
AU - Cormet-Boyaka, Estelle
AU - Hong, Jeong S.
AU - Berdiev, Bakhram K.
AU - Fortenberry, James A.
AU - Rennolds, Jessica
AU - Clancy, J. P.
AU - Benos, Dale J.
AU - Boyaka, Prosper N.
AU - Sorscher, Eric J.
PY - 2009
Y1 - 2009
N2 - Cystic fibrosis (CF) is most frequently associated with deletion of phenylalanine at position 508 (ΔF508) in the CF transmembrane conductance regulator (CFTR) protein. The ΔF508-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 ΔF508-CFTR in vivo. cDNA encoding CFTR fragments were delivered to human airway epithelial cells and mice harboring endogenous ΔF508-CFTR. Delivery of small CFTR fragments, which do not act as chloride channels by themselves, rescue ΔF508-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 ΔF508-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 ΔF508 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.
AB - Cystic fibrosis (CF) is most frequently associated with deletion of phenylalanine at position 508 (ΔF508) in the CF transmembrane conductance regulator (CFTR) protein. The ΔF508-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 ΔF508-CFTR in vivo. cDNA encoding CFTR fragments were delivered to human airway epithelial cells and mice harboring endogenous ΔF508-CFTR. Delivery of small CFTR fragments, which do not act as chloride channels by themselves, rescue ΔF508-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 ΔF508-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 ΔF508 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.
KW - Cystic fibrosis
KW - In vivo rescue
KW - Processing
KW - Transcomplementation
UR - http://www.scopus.com/inward/record.url?scp=70350550448&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=70350550448&partnerID=8YFLogxK
U2 - 10.1096/fj.08-127878
DO - 10.1096/fj.08-127878
M3 - Article
VL - 23
SP - 3743
EP - 3751
JO - FASEB Journal
JF - FASEB Journal
SN - 0892-6638
IS - 11
ER -