Functional Rescue of DeltaF508-CFTR by Peptides Designed to Mimic Sorting Motifs

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• 作者：Patrick Kim Chiaw ; Ling-Jun Huan ; Stephane Gagnon ; Diane Ly ; Neil Sweezey ; Daniela Rotin ; Charles M. Deber ; Christine E. Bear
• 刊名：Chemistry & Biology
• 出版年：2009
• 出版时间：29 May 2009
• 年：2009
• 卷：16
• 期：5
• 页码：520-530
• 全文大小：984 K

文摘

Summary

The cystic fibrosis (CF)-causing mutant, deltaF508-CFTR, is misfolded and fails to traffic out of the endoplasmic reticulum (ER) to the cell surface. Introduction of second site mutations that disrupt a diarginine (RXR)-based ER retention motif in the first nucleotide binding domain rescues the trafficking defect of deltaF508-CFTR, supporting a role for these motifs in mediating ER retention of the major mutant. To determine if these RXR motifs mediate retention of the native deltaF508-CFTR protein in situ, we generated peptides that mimic these motifs and should antagonize mistrafficking mediated via their aberrant exposure. Here we show robust rescue of deltaF508-CFTR in cell lines and in respiratory epithelial tissues by transduction of RXR motif-mimetics, showing that abnormal accessibility of this motif is a key determinant of mistrafficking of the major CF-causing mutant.