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First published online January 24, 2007

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When quality control goes awry

The majority of cystic fibrosis (CF) sufferers have a point mutation (F508) in the CTFR ion channel that impairs its assembly. The mutant protein eludes the ER and is cleared from the distal secretory pathway by lysosomal degradation. CF cells accumulate free cholesterol similar to that seen in Niemann-Pick disease and this was attributed to lack of CFTR function. Now Martina Gentzsch et al. (p. 447) report that lipid accumulation in CF cells is due to the presence of misfolded CFTR rather than lack of its activity. They find that the expression of misassembled mutant CFTR proteins in the distal secretory pathway causes a disruption in cholesterol trafficking. Cholesterol and glycosphingolipids accumulate in punctate endosomal structures and levels of cholesterol esters are reduced, which indicates a block in cholesterol translocation. Expression of the small GTPase Rab9 can overcome this defect in lipid trafficking. Interestingly, misassembled forms of the multidrug-resistance-associated protein 1 (MRP1) behave similarly. This raises the possibility that escape of misassembled mutant proteins from quality control in the ER has a more general impact on lipid homeostasis in endocytic compartments.

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Related articles in JCS:

Misassembled mutant F508 CFTR in the distal secretory pathway alters cellular lipid trafficking

Martina Gentzsch, Amit Choudhury, Xiu-bao Chang, Richard E. Pagano, and John R. Riordan
JCS 2007 120: 447-455. [Abstract] [Full Text]  

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Related articles in JCS Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Search for Related Content Social Bookmarking                         What's this?