Abstract
In cystic fibrosis (CF), the most frequent mutant variant of the cystic fibrosis transmembrane conductance regulator (CFTR), F508del-CFTR protein, is misfolded and retained in the endoplasmic reticulum (ER). We previously showed that the unfolded protein response (UPR) may be triggered in CF. Since prolonged UPR activation leads to apoptosis via the calcium-calpain-caspase-12-caspase-3 cascade and because apoptosis is altered in CF, our aim was to compare the ER stress-induced apoptosis pathway between wild type (Wt) and F508del-CFTR expressing cells. Here we show that the calcium-calpain-caspase-12-caspase-3 cascade is altered in F508del-CFTR expressing cells. We propose that this alteration is involved in the altered apoptosis triggering observed in CF.
Highlights
Cystic fibrosis (CF) is the most common lethal autosomal recessive disease in the Caucasian population
According to unfolded protein response (UPR) triggering in CF, our aim was to assess whether the [Ca2+]i, Cal-1, Cal-2, Csp-12 and Csp-3 cascade activation was modified in F508del-CFTR expressing cells when compared to wt-CFTR expressing cells
The most common mutation F508del-CFTR, whose pathology is primarily due to a decrease in Cl permeability through the CFTR
Summary
Cystic fibrosis (CF) is the most common lethal autosomal recessive disease in the Caucasian population. It is due to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene [1,2,3]. The misfolded F508del-CFTR protein does not traffic correctly to the plasma membrane and is degraded by proteasome [4,5,6,7,8,9,10,11]. Beside the accumulation of F508del-CFTR in the ER, inflammation and infection are the major features of CF [13]. Eukaryotic cells respond to the accumulation of misfolded proteins in the ER, to inflammation and infection by activating the unfolded protein response (UPR) [14,15]. Some lines of evidence suggest that UPR is triggered in F508del-CFTR expressing cells due to the mutated protein itself or by exogenous factors [16,17,18,19]. Whereas it is an adaptive process aimed to restore the ER homeostasis, it may lead to apoptosis due to an increased intracellular calcium ([Ca2+]i) content followed by the activation of the calpain (Cal-1 and -2), caspase (Csp) -12 and Csp-3 cascade [25,26,27,28,29,30,31]
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