Role of N-linked oligosaccharides in the biosynthetic processing of the cystic fibrosis membrane conductance regulator

Xiu-Bao D Chang, April Mengos, Yue Xian Hou, Liying Cui, Timothy J. Jensen, Andrei Aleksandrov, John R. Riordan, Martina Gentzsch

Research output: Contribution to journalArticle

53 Scopus citations

Abstract

The epithelial chloride channel CFTR is a glycoprotein that is modified by two N-linked oligosaccharides. The most common mutant CFTR protein in patients with cystic fibrosis, ΔF508, is misfolded and retained by ER quality control. As oligosaccharide moieties of glycoproteins are known to mediate interactions with ER lectin chaperones, we investigated the role of N-linked glycosylation in the processing of wild-type and ΔF508 CFTR. We found that N-glycosylation and ER lectin interactions are not major determinants of trafficking of wild-type and ΔF508 from the ER to the plasma membrane. Unglycosylated CFTR, generated by removal of glycosylation sites or treatment of cells with the N-glycosylation inhibitor tunicamycin, did not bind calnexin, but did traffic to the cell surface and exhibited chloride channel activity. Most importantly, unglycosylated ΔF508 CFTR still could not escape quality control in the early secretary pathway and remained associated with the ER. However, the absence of N-linked oligosaccharides did reduce the stability of wild-type CFTR, causing significantly more-rapid turnover in post-ER compartments. Surprisingly, the individual N-linked carbohydrates do not play equivalent roles and modulate the fate of the wild-type protein in different ways in its early biosynthetic pathway.

Original languageEnglish (US)
Pages (from-to)2814-2823
Number of pages10
JournalJournal of Cell Science
Volume121
Issue number17
DOIs
StatePublished - Sep 1 2008

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Keywords

  • Calnexin
  • CFTR
  • EDEM
  • Glycoprotein
  • Glycosylation
  • Processing

ASJC Scopus subject areas

  • Cell Biology

Cite this

Chang, X-B. D., Mengos, A., Hou, Y. X., Cui, L., Jensen, T. J., Aleksandrov, A., Riordan, J. R., & Gentzsch, M. (2008). Role of N-linked oligosaccharides in the biosynthetic processing of the cystic fibrosis membrane conductance regulator. Journal of Cell Science, 121(17), 2814-2823. https://doi.org/10.1242/jcs.028951