Targeting the EGFR-ERK axis using the compatible solute ectoine to stabilize CFTR mutant F508del

Autor: Jack Wellmerling, Rachael E. Rayner, Sheng‐Wei Chang, Elizabeth L. Kairis, Sun Hee Kim, Amit Sharma, Prosper N. Boyaka, Estelle Cormet‐Boyaka
Rok vydání: 2022
Předmět:
Zdroj: FASEB J
ISSN: 1530-6860
Popis: Mutations in the CFTR gene lead to cystic fibrosis, a genetic disease associated with chronic infection and inflammation and ultimately respiratory failure. The most common CF-causing mutation is F508del and CFTR modulators (correctors and potentiators) are being developed to rescue its trafficking and activity defects. However, there are currently no modulators that stabilize the rescued membrane F508del-CFTR which is endocytosed and quickly degraded resulting in a shorter half-life than wild-type (WT). We previously reported that the extracellular signal-regulated kinase (ERK) MAPK pathway is involved in CFTR degradation upon cigarette smoke exposure. Interestingly, we found that ERK phosphorylation was increased in CF human bronchial epithelial (HBE) cells (CF-HBE41o- and primary CF-HBE) compared to non-CF controls, and this was likely due to signaling by the epidermal growth factor receptor (EGFR). EGFR can be activated by several ligands, and we provide evidence that amphiregulin (AREG) is important for activating this signaling axis in CF. The natural osmolyte ectoine stabilizes membrane macromolecules. We show that ectoine decreases ERK phosphorylation, increases the half-life of rescued CFTR, and increases CFTR-mediated chloride transport in combination with the CFTR corrector VX-661. Additionally, ectoine reduces production of AREG and interleukin-8 by CF primary bronchial epithelial cells. In conclusion, EGFR-ERK signaling negatively regulates CFTR and is hyperactive in CF, and targeting this axis with ectoine may prove beneficial for CF patients.
Databáze: OpenAIRE