The Interplay between the Unfolded Protein Response, Inflammation and Infection in Cystic Fibrosis

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.

Automated summary

The most common mutation in cystic fibrosis is p.Phe508del in the CFTR gene, leading to retention and rapid degradation of CFTR protein in the endoplasmic reticulum, triggering an atypical Unfolded Protein Response (UPR). There is still debate on the role of UPR in CF, whether it is triggered by accumulation of misfolded CFTR proteins or as a result of inflammation and infection in the disease.