A new study from The Hospital for Sick Children (SickKids) reveals the process underlying protein organisation on cell membranes, a finding that could pave the way for innovative cystic fibrosis treatments.

The study is published in the journal Proceedings of the National Academy of Sciences.

Cystic fibrosis (CF) is a genetic condition that affects the lungs, pancreas and other organs, caused by variations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. There are around 700 known variants that cause CF, but current treatments address only a few, and none offer a cure.

"Therapeutics for cystic fibrosis have hit a plateau, demanding that we uncover new ways of looking at the science behind the condition. By studying protein organisation, we've uncovered a brand-new avenue for developing therapeutics for cystic fibrosis," says Dr. Jonathon Ditlev, Scientist in the Molecular Medicine and Cell & Systems Biology programs.

Phase separation key to CFTR protein

Rather than looking solely at the function of the CFTR protein, the study examined how CFTR proteins are organised on the cell membrane. In healthy children, the proteins form clusters, helping to regulate water and salt intake. In people with CF, those clusters are disrupted.

The process that forms the clusters is called phase separation, a well-known process that has recently been appreciated for its role in biological organisation. Dr. Julie Forman-Kay, Program Head and Senior Scientist in the Molecular Medicine program and co-lead author of the paper, has proposed that it might be relevant to CFTR in 2017.

"Our findings establish CFTR as a phase-separating protein, opening up a previously unexplored mode of protein regulation and a new target for future therapies," explains Forman-Kay.

The future of CF therapeutics—inspired by the past

The research team is already working with other SickKids scientists, including Dr. Christine Bear, Co-Director of the Cystic Fibrosis Centre, to explore ways to advance this research into novel therapies for CF.

"Current therapies for cystic fibrosis are effective for most children, but not all," says Bear, who is also a Senior Scientist in the Molecular Medicine program. "These findings could help us target those for whom current therapies remain ineffective, while also bolstering outcomes for all those affected by CF."

While the study could inform the next generation of CF therapeutics and advance Precision Child Health at SickKids, Ditlev joined SickKids without any thought of researching CF—but that quickly changed.

"Being a part of SickKids, with its storied history of research excellence impacting patients with cystic fibrosis, I realised how my experience and tools could contribute to and enhance this legacy."

More information: Yimei Wan et al, Protein interactions, calcium, phosphorylation, and cholesterol modulate CFTR cluster formation on membranes, Proceedings of the National Academy of Sciences (2025). DOI: 10.1073/pnas.2424470122