New Insights into the Defective Protein Linked to Cystic Fibrosis

New Insights into the Defective Protein Linked to Cystic Fibrosis

Researchers at the National Health Institute, Doutor Ricardo Jorge and the University of Lisboa in Portugal recently published in the journal Science Signaling new insights into the processing of the cystic fibrosis transmembrane conductance regulator (CFTR) protein and possible new therapeutic targets for cystic fibrosis. The study is entitled “A molecular switch in the scaffold NHERF1 enables misfolded CFTR to evade the peripheral quality control checkpoint.

Cells have a peripheral protein quality control (PPQC) checkpoint system that removes proteins that are misfolded from the cell plasma membrane. This mechanism targets the defective proteins for degradation, preventing the accumulation of dysfunctional proteins in the cell surface. The absence of certain membrane proteins is the cause of several human diseases. Sometimes, the misfolded protein still has some functionality, and if this protein is able to circumvent the PPQC and reach the cell surface, it can potentially lessen disease severity. The CFTR protein is an example of this possibility.

Mutations in the CFTR gene can cause cystic fibrosis, a life-threatening genetic disease characterized by the formation of unusually thick, sticky mucus that can result in serious respiratory and gastrointestinal manifestations. There is no cure for CF and in approximately 85% of the cases the disease is caused by a specific CFTR mutation – F508del. This mutation yields a CFTR protein that is partially functional.

A small number of compounds called “correctors” have been previously reported to be able to partially rescue the trafficking of F508del-CFTR to the plasma membrane. One of these promising compounds is VX-809 (lumacaftor), however, when tested in clinical trials, VX-809 showed limited success, and it is thought that this result is due to the PPQC activity.

In the study, researchers assessed the PPQC checkpoint in lung epithelial cells with F508del-CFTR after exposure to VX-809. Researchers found that the conformation of a scaffold protein called NHERF1 (Na+/H+ exchange regulatory factor 1) was crucial in PPQC recognition of the rescued F508del-CFTR. They found that activation of the cytoskeletal regulator Rac1 promotes the interaction between the actin-binding adaptor protein ezrin and NHERF1, which triggers a conformational change in NHERF1 enabling it to interact with the rescued F508del-CFTR. This complex blocks the recruitment of the E3 ubiquitin ligase CHIP (carboxyl terminus of Hsc70 interacting protein) that normally targets the defective F508del-CFTR protein for degradation. In this way, F508del-CFTR is no longer sent for degradation but retained at the cell surface. The team reported that the co-exposure to Rac1 activator almost tripled VX-809 efficacy in primary airway epithelial cells from patients with F508del mutation.

The team concluded that activation of ezrin by Rac1 signaling induces a conformational change in NHERF1, which makes it able to bind and stabilize the misfolded F508del-CFTR at the plasma membrane. The authors suggest that these findings offer potential new targets for cystic fibrosis treatment and could eventually help make experimental therapies such as lumacaftor more effective.

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