Etiological involvement of CFTR in apparently unrelated human diseases

摘要

Cystic fibrosis transmembrane conductance regulator (CFTR) is an ATP-gated channel that regulates anion fluxes across the plasma membrane of multiple cell types. Loss-of-function mutations of cause the most frequent human monogenetic lethal disease, cystic fibrosis (CF). The pathogenesis of CF involves two complementary phenomena. On one hand, failure to transport chloride anions into the extracellular space increases the viscosity and thickness of mucus, hence compromising its elimination from the respiratory tract (which facilitates chronic inflammation coupled to recurrent pulmonary infections) and the pancreatic ducts (which drives failure of the exocrine pancreas and consequent nutrient malabsorption). On the other hand, imbalances in intracellular anion fluxes (perhaps combined with deficient CFTR scaffold functions) favor a progressive and irreversible imbalance in proteostasis due to activation of transglutaminase 2 (TGM2) and reduced beclin 1 (BECN1) expression, culminating with inhibition of autophagy. These three phenomena (deficient CFTR function, TGM2 activation, and autophagy impairment) amplify each other in a feed-forward circuitry, locking affected cells in a close-to-irrevocable pro-inflammatory state that contributes to disease pathogenesis. Inhibiting each of the cornerstones of this triad can improve CF pathogenesis, as demonstrated by clinical trials using CFTR-stimulatory agents (so-called “CFTR potentiators”), TGM2 inhibitors, and autophagy enhancers. However, it should be noted that the efficacy of these agents is largely dependent on the exact molecular characteristics of the pathogenic CFTR variant. Thus, CFTR potentiators can only improve CFTR functions when the defective protein is expressed on the plasma membrane and possesses residual chloride channel activity. In contrast, cysteamine, a TGM2 inhibitor, and epigallocatechin gallate (EGCG), an autophagy activator, can only synergize at improving CFTR functions if the mutant protein can be rescued from premature degradation or accelerated turnover, thus favoring its reappearance at the plasma membrane. This effect can also be obtained by so-called “CFTR correctors.” Thus, the precise CFTR defect that accounts for CF (amongst up to 2000 distinct pathogenic mutations described so far) dictates the pharmacological agents that should be used for the optimal treatment of a specific patient. That said, it appears that patients bearing the most frequent mutation leading to the deletion of phenylalanine at position 506 ( del506), which accounts for 70–90% of CF cases, respond well to the combination of EGCG and cysteamine.