SFPQ Protein Helps to Restore CFTR in Cells With Common Mutation

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Increasing the levels of the SFPQ protein helped to restore expression and function of the CFTR protein in cells with a F508del mutation in the CFTR gene, the most common cause of cystic fibrosis (CF).

Work also showed that SFPQ levels were unusually low in these cells, suggesting this protein “may play a role in CF lung disease,” its researchers wrote.

The study, “SFPQ rescues F508del-CFTR expression and function in cystic fibrosis bronchial epithelial cells, was published in the journal Scientific Reports

Normally, the CFTR protein acts like a gate on the surface of cells, helping to regulate the flow of ions and water in and out of them. But mutations in the CFTR gene, which codes for the protein, either cause CFTR to be defective or entirely absent. F508del, the most frequent CF-causing mutation, is found in about nine out of every 10 CF patients.

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SFPQ — short for splicing factor proline/glutamine-rich — is an RNA-binding protein that helps to regulate a variety of cell functions; in particular, it is involved in several processes by which cells “read” genes to make proteins. The SFPQ protein has been shown to play a role in some diseases, including cancer and genetic disorders.

A team of scientists, led by those at a U.S. government institute, conducted a series of experiments to examine whether this protein might play a role in CF caused by the F508del mutation.

“Whether SFPQ has any role in the regulation of CF lung disease is completely unknown,” the team wrote.

The researchers first assessed SFPQ levels in CF cells and samples of patients’ lung tissue, finding that levels of this protein were substantially reduced in cells harboring mutated CFTR, suggesting that the SFPQ protein could be involved in CF lung disease.

“This is the first report of an aberrant reduction in SFPQ protein levels in CF lung epithelial cells,” they wrote.

By genetically manipulating cell models, the scientists next examined the effect of increasing SFPQ levels in cells with the F508del mutation. Results showed that higher SFPQ levels led to more CFTR protein on the surface of cells. CFTR activity, as measured by the movement of chloride ions, also improved.

“Not only does increased levels of SFPQ promote increased expression of mutant CFTR,” the investigators added, “but it also drives more of the mutant CFTR protein to the plasma [cell] membrane and rescues the function of [the mutated protein] in CF lung epithelial cells.”

How the higher SFPQ levels influenced cells’ gene expression — that is, the extent to which different genes are “turned on” or “turned off” within a cell — was examined next. Notably, prior studies had identified proteins produced by some of these genes as regulators of CFTR activity. Cell functions seen to be altered by SFPQ included cell death, survival, growth, and development.

“These SFPQ-mediated modulations in gene expression to regulate molecular and cellular-functions likely contributed to increasing expression, relocation and restore the function of [the mutated protein] in [CF] cells,” the researchers concluded.

Further studies into how the CFTR protein is regulated may pave the way for future treatments targets in CF, they added.

“Multiple processes, in which SFPQ plays a central role, are operating in concert to regulate CF lung diseases,” the researchers wrote. “Understanding these mechanisms will lead to novel epigenetic therapeutic targets for CF and related pulmonary diseases.”