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- Title
Multiple Molecular Chaperone-mediated Pharmacologic Rescue of δF508-CFTR from ERAD.
- Authors
Singh, Om V.; Zeitlin, Pamela L.
- Abstract
Cystic Fibrosis (CF) is an autosomal recessive disorder caused by dysfunction or absence of a single membrane glyeoprotein chloride channel, the CF transmembrane conductance regulator (CFTR). Mutant AF508, retained in the ER, and degraded by the ubiquitin-proteasome pathway. 4-phynylbutyrate (4-PBA) can rescue ΔF508-CFTR. Goal of this study was to identify the proteins interacting with CFTR during CFTR-transit from ER to the plasma membrane (PM). We hypothesize, a subset of proteins interacting to CFTR during restoration of ΔF508-CFTR, will correlate with proteins binding to wtCFTR. Cellular lysates from IB3-1, CF bronchial epithelial cells (ΔF508/W 1282X), non-CF (corrected 1B3-1 by wtCFTR, $9) and rescued-CF (4-PBA treated IB3-1) were collected and immunoprecipitated using anti-CFTR 169 antisera, and resolved on 2-DE. Differentially expressed proteins were identified by PMF using MALDI-TOF. A subset of HSP70 family members were tracked at sub-cellular compartments (ER, Cytosol and PM). Significant Z scores and maximum coverage included for GRP(s) 94, 78, 75, 58, HSP(s) 84, 70, 27, HSC70, Vimentin and KRT18. Connectivity map shows multiple ER-network proteins were interacted with CFTR through either regulation or signaling pathways. Multiple ER-chaperones (GRPs94, 78, 75, 58 and HSP84) interacted with B form of CFTR (160 kDa) in ER, but not with folded C form of CFTR (180 kDa) in the PM. 4-PBA rescued CFTR associated with changes in the network of ER and cytosolic chaperones mimics patterns of proteins interacted with wtCFTR.
- Subjects
MOLECULAR chaperones; PHARMACOLOGY; CYSTIC fibrosis; PROTEINS; GENETIC disorders
- Publication
FASEB Journal, 2007, Vol 21, Issue 5, pA420
- ISSN
0892-6638
- Publication type
Article