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Mechanism of disease

aggresomes of Beclin1, one of the key proteins in autophagy. Defective autophagy in turn induces decreased clearance of aggresomes, accumulation of damaged mitochondria, proteasome overload, and contributes to the pro- inflammatory vicious cycle.12

CFTR and proteostasis As described above, folding and maintenance of CFTR as a functional chloride channel needs sophisticated proteostasis network (PN) to promote domain folding and interdomain assembly. The continuous balance between folding efficiency and degradation is required to regulate ER stress and misfolded protein overload, and results in a protein biogenesis homeostasis. Therefore, continuously synthesised abnormal CFTR deregulates proteome homeostasis and consequently all the signaling pathways, which sense the CFTR folding state, trafficking, aggregation/disaggregation and degradation systems.13

A growing body of evidence suggests that proteins interacting with F508del CFTR regulate its trafficking, degradation and function. It has been reported that interrupting such interaction promotes the delivery of F508del CFTR to the plasma membrane.14

Moreover, the

defective CFTR in cells where it is endogenously expressed impacts on many other cellular processes. For example, the oxidative stress induced by mutated CFTR leads to mitochondrial defects and abnormal levels of mitochondrial glutathione, followed by the increased production of IL-8.15

Furthermore, it has

been proposed that CFTR could control vesicular trafficking, modulate intracellular and organellar pH, regulate protein glycosylation and prenylation and be a gene of development during foetal life.

Conclusions 10

Although the relationship between precise mechanisms of CF disease and CFTR dysfunction still remain unclear, a better understanding of CFTR mutations now points to novel therapies. They target inflammatory pathways, transepithelial ionic transport and, more recently, the underlying basic defects responsible for CFTR protein loss-of-function, such as mutation-targeted strategies. Recent mutation-specific therapy clinical trials indeed have displayed spectacular improvement in clinical status of patients. Such studies are convincing that

“It has been proposed that CFTR could control vesicular trafficking, modulate intracellular and organellar pH and be a gene of development during foetal life”

innovative treatment can ultimately make a difference in the clinical setting and provide considerable hope for the future. l

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12. Luciani A et al. Defective CFTR induces aggresome formation and lung inflammation in cystic fibrosis through ROS-mediated autophagy inhibition. Nat Cell Biol 2010;12(9):863–75.

13. Balch WE, Roth DM, Hutt DM. Emergent properties of proteostasis in managing cystic fibrosis. Cold Spring Harb Perspect Biol 2011;3:a004499.

14. Odolczyk N et al. Discovery of novel potent ∆F508-CFTR correctors that target the nucleotide binding domain. EMBO Mol Med 2013. [Epub ahead of print] .

15. Kelly-Aubert M et al. GSH monoethyl ester rescues mitochondrial defects in cystic fibrosis models. Hum Mol Genet 2011;20(14):2745–59.

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