Abstract
In cystic fibrosis (CF), p.Phe508del is the most frequent mutation in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene. The p.Phe508del-CFTR protein is retained in the ER and rapidly degraded. This retention likely triggers an atypical Unfolded Protein Response (UPR) involving ATF6, which reduces the expression of p.Phe508del-CFTR. There are still some debates on the role of the UPR in CF: could it be triggered by the accumulation of misfolded CFTR proteins in the endoplasmic reticulum as was proposed for the most common CFTR mutation p.Phe508del? Or, is it the consequence of inflammation and infection that occur in the disease? In this review, we summarize recent findings on UPR in CF and show how infection, inflammation and UPR act together in CF. We propose to rethink their respective role in CF and to consider them as a whole.
Highlights
Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CysticFibrosis Transmembrane Conductance Regulator (CFTR) gene [1]
The CFTR protein belongs to the adenosine triphopsphate (ATP)-binding cassette (ABC) transporter’s family and mainly acts as a cAMP-regulated chloride (Cl− )
The p.Phe508del-CFTR protein remains in a coreglycosylated form in the endoplasmic reticulum (ER) and only a negligible quantity is expressed at the plasma membrane of the cells [6,7]
Summary
Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the Cystic. The p.Phe508del-CFTR protein remains in a coreglycosylated form in the ER and only a negligible quantity is expressed at the plasma membrane of the cells [6,7] This is still subject to debate, the retention and/or the accumulation of the p.Phe508del-CFTR protein within the ER likely induces an ER stress leading to the triggering of the Unfolded Protein Response (UPR). It is not known how the increased p.Phe508del-CFTR expression might affect the UPR but the overexpression of recombinant p.Phe508del-CFTR induces ER stress and activated the UPR [15,16] Another evidence that UPR is present in CF cells is that the IRE1α mRNA levels are upregulated in freshly isolated CF human bronchial epithelial cells when compared to normal epithelial cells [17]. We propose that the UPR is as important as inflammation and infection in CF, and that the three of them should be considered at the same level because they interplay
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