期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 286, 期 24, 页码 21239-21253出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M111.240267
关键词
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资金
- National Institutes of Health, NIDDK [R01 DK058046, R01 DK073185]
- NHLBI [R01 HL059959, K08 HL081080]
- American Pediatric Society-Society for Pediatric Research [T35 HD0744]
- American Heart Association
- Cystic Fibrosis Foundation
- Lottery Health Research New Zealand
- Melbourne Research Unit for Facial Disorders
Sodium 4-phenylbutyrate (4PBA) improves the intracellular trafficking of Delta F508-CFTR in cystic fibrosis (CF) epithelial cells. The underlying mechanism is uncertain, but 4PBA modulates the expression of some cytosolic molecular chaperones. To identify other 4PBA-regulated proteins that might regulate Delta F508-CFTR trafficking, we performed a differential display RT-PCR screen on IB3-1 CF bronchiolar epithelial cells exposed to 4PBA. One transcript up-regulated by 4PBA encoded ERp29, a luminal resident of the endoplasmic reticulum (ER) thought to be a novel molecular chaperone. We tested the hypothesis that ERp29 is a 4PBA-regulated ER chaperone that influences Delta F508-CFTR trafficking. ERp29 mRNA and protein expression was significantly increased (similar to 1.5-fold) in 4PBA-treated IB3-1 cells. In Xenopus oocytes, ERp29 overexpression increased the functional expression of both wild-type and Delta F508-CFTR over 3-fold and increased wild-type cystic fibrosis transmembrane conductance regulator (CFTR) plasma membrane expression. In CFBE41o- WT-CFTR cells, expression of and short circuit currents mediated by CFTR decreased upon depletion of ERp29 as did maturation of newly synthesized CFTR. In IB3-1 cells, Delta F508-CFTR co-immunoprecipitated with endogenous ERp29, and overexpression of ERp29 led to increased Delta F508-CFTR expression at the plasma membrane. These data suggest that ERp29 is a 4PBA-regulated ER chaperone that regulates WT-CFTR biogenesis and can promote Delta F508-CFTR trafficking in CF epithelial cells.
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