People with cystic fibrosis suffer from persistent infections and mucus build-up in the lungs. While there are treatments to deal with the symptoms--such as antibiotics for infections--there are no therapies that fully restore lung function.
Most patients with cystic fibrosis have a mutation, called ΔF508, in the gene that encodes cystic fibrosis transmembrane conductance regulator (CFTR), keeping CFTR from folding properly and being processed correctly in cells. Interestingly, previous studies showed that mutant CFTR regains normal functions at low temperatures.
In the new study published int he journal Nature, the researchers analyzed cell samples with a tool called Co-Purifying Protein Identification Technology (CoPIT), a new method they developed to identify proteins and analyze data. With CoPIT, they identified almost every protein CFTR interacted with--even tracking the secondary and tertiary protein interactions.
The results were surprising. While it was thought that most mutant proteins just lack one or two crucial interactions, the ΔF508 CFTR mutant had acquired an entirely new "disease-specific" interaction network.
"Three hundred proteins changed their level of interaction, and an additional 200 proteins interacted with the mutated CFTR," said Pankow. "It's like the wrong people are talking to the mutated CFTR all the time."
The researchers narrowed these mutant protein interactions to just eight key disruptive proteins. The team then used a gene silencing approach to remove or "knock down" those proteins and block the interaction of these proteins with ΔF508 CFTR. They found that without the additional interactions, ΔF508 CFTR partially returned to normal function.