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The toxin of pseudomonas aeruginosa pyocyanin induces lysosomal degradation of CFTR: Consequences for strategies to correct ΔF508‐CFTR
Author(s) -
CormetBoyaka Estelle,
Chang ShengWei,
Balsiger Robert,
Boyaka Prosper
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1223.22
Subject(s) - cystic fibrosis , mapk/erk pathway , pseudomonas aeruginosa , pyocyanin , cystic fibrosis transmembrane conductance regulator , δf508 , chemistry , microbiology and biotechnology , signal transduction , biology , biochemistry , gene , bacteria , virulence , genetics , quorum sensing
CFTR plays a key role in maintenance of lung fluid homeostasis. Mutations in the cftr gene resulting in defects in CFTR protein and/or function lead to cystic fibrosis (CF), a genetic disease associated with chronic infection and inflammation. Pseudomonas aeruginosa (P. aeruginosa) is the major pathogen in the lung of CF patients. One of the toxins produced by P. aeruginosa is pyocyanin (PCN), a redox‐active metabolite. PCN was shown to impair CFTR chloride transport but the mechanism is still unclear. We have evidence that PCN decreases CFTR expression by inducing its lysosomal degradation in human bronchial epithelial cells. Since we recently reported that activation of the ERK signaling pathway by cigarette smoke negatively regulates CFTR expression, we investigated whether PCN impairs CFTR expression via activation of the ERK MAPK pathway. Our results show that PCN induces activation of the ERK pathway in human bronchial epithelial cells. Inhibition of the ERK MAPK pathway using specific inhibitors prevented the PCN‐induced reduction of CFTR protein. Conversely, inhibition of the JNK or P38 MAPK pathways had no protective effect. Pharmacological compounds are being developed to rescue the processing defect of the most common CF‐causing mutant, ΔF508‐CFTR. We hypothesized that PCN, which is abundantly present in the lung of CF patients, will hamper the beneficial effect of CFTR correctors. CFBE cells, a human bronchial cell line derived from a CF patient, were treated with the corrector VX‐661 which allowed rescue of ΔF508‐CFTR as observed by detection of mature (Band C) CFTR. Addition of PCN resulted in the loss of rescued‐CFTR. Interestingly, presence of MEK/ERK inhibitor was able to prevent decrease of mature CFTR induced by PCN. Our results indicate that PCN present in the lung of CF patients could hamper correction of ΔF508‐CFTR and identify the MEK/ERK pathway as a new molecular target. Support or Funding Information NIH