Cystic fibrosis - a multiorgan protein misfolding disease

Abstract

Cystic fibrosis (CF) is a heterogeneous multiorgan disease caused by mutations in the CFTR gene leading to misfolding (and other defects) and consequent dysfunction of CFTR protein. The majority of mutations cause a severe CF phenotype, and people with this condition will require a wide variety of medical interventions and therapies throughout their lives to address the symptoms of their condition. CF affects many different organ systems, but the most serious consequence of the disease is degeneration of lung function due to chronic respiratory infection and colonization of the airways with opportunistic microbial pathogens. Improvements in therapeutics, particularly the effective use of antibiotics, have led to significant gradual increases in life expectancy. There remains, however, a continuing need for newer, safer and more effective antimicrobials and mucolytic agents to maintain and improve our ability to combat CF lung infections before other curative approaches which target the root cause of the disease become available.

Keywords: CFTR; Pseudomonas aeruginosa; bacterial biofilms; cystic fibrosis; lung infection; respiratory disease.

Figure 1.. Class I mutations (such as G542X) lead to the premature termination of CFTR protein translation.

Class II mutations include the common F508del (or ΔF508) which lead to the misfolding of CFTR protein and subsequent polyubiquitination and destruction by the cell proteasome. Class III mutations (such as G551D) are also misfolded, but may be transported to the plasma membrane. They are either poorly regulated or nonfunctional and are subsequently degraded by the cell. Class IV mutations lead to a receptor with reduced chloride conductance, whilst class V mutations lead to reduced expression levels of CFTR. Class VI mutations lead to a higher turnover of CFTR at the plasma membrane. Class IV, V and VI mutations lead to a nonclassical or atypical CF phenotype and are not shown.