Misassembled mutant ΔF508 CFTR in the distal secretory pathway alters cellular lipid trafficking

Martina Gentzsch, Amit Choudhury, Xiu-Bao D Chang, Richard E. Pagano, John R. Riordan

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

Most patients with cystic fibrosis (CF) have a single codon deletion (ΔF508) in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) that impairs assembly of the multidomain glycoprotein. The mutant protein escapes endoplasmic reticulum (ER) quality control at low temperature, but is rapidly cleared from the distal secretory pathway and degraded in lysosomes. CF cells accumulate free cholesterol similar to Niemann-Pick disease type C cells. We show that this lipid alteration is caused by the presence of misassembled mutant CFTR proteins, including ΔF508, in the distal secretory pathway rather than the absence of functional CFTR. By contrast, cholesterol distribution is not changed by either D572N CFTR, which does not mature even at low temperature, or G551D, which is processed normally but is inactive. On expression of the ΔF508 mutant, cholesterol and glycosphinglipids accumulate in punctate endosomal structures and cholesterol esters are reduced, indicating a block in the translocation of cholesterol to the ER for esterification. This is overcome by Rab9 overexpression, resulting in clearance of accumulating intracellular cholesterol. Similar but less pronounced alterations in intracellular cholesterol distribution are observed on expression of a temperature-rescued mutant variant of the related ATP-binding cassette (ABC) protein multidrug resistance-associated protein 1 (MRP1). Thus, on escape from ER quality control, misassembled mutants of CFTR and MRP1 impair lipid homeostasis in endocytic compartments.

Original languageEnglish (US)
Pages (from-to)447-455
Number of pages9
JournalJournal of Cell Science
Volume120
Issue number3
DOIs
StatePublished - Feb 1 2007

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Cystic Fibrosis Transmembrane Conductance Regulator
Secretory Pathway
Cholesterol
Lipids
Endoplasmic Reticulum
Cystic Fibrosis
Quality Control
Temperature
Type C Niemann-Pick Disease
Cholesterol Esters
Esterification
Mutant Proteins
Lysosomes
Codon
Glycoproteins
Carrier Proteins
Homeostasis
Adenosine Triphosphate
Genes
Proteins

Keywords

  • CFTR
  • Cholesterol
  • Cystic fibrosis
  • Glycosphingolipids
  • Lipid trafficking

ASJC Scopus subject areas

  • Cell Biology

Cite this

Gentzsch, M., Choudhury, A., Chang, X-B. D., Pagano, R. E., & Riordan, J. R. (2007). Misassembled mutant ΔF508 CFTR in the distal secretory pathway alters cellular lipid trafficking. Journal of Cell Science, 120(3), 447-455. https://doi.org/10.1242/jcs.03350

Misassembled mutant ΔF508 CFTR in the distal secretory pathway alters cellular lipid trafficking. / Gentzsch, Martina; Choudhury, Amit; Chang, Xiu-Bao D; Pagano, Richard E.; Riordan, John R.

In: Journal of Cell Science, Vol. 120, No. 3, 01.02.2007, p. 447-455.

Research output: Contribution to journalArticle

Gentzsch, M, Choudhury, A, Chang, X-BD, Pagano, RE & Riordan, JR 2007, 'Misassembled mutant ΔF508 CFTR in the distal secretory pathway alters cellular lipid trafficking', Journal of Cell Science, vol. 120, no. 3, pp. 447-455. https://doi.org/10.1242/jcs.03350
Gentzsch, Martina ; Choudhury, Amit ; Chang, Xiu-Bao D ; Pagano, Richard E. ; Riordan, John R. / Misassembled mutant ΔF508 CFTR in the distal secretory pathway alters cellular lipid trafficking. In: Journal of Cell Science. 2007 ; Vol. 120, No. 3. pp. 447-455.
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