The cellular system that degrades faulty proteins created by the cystic fibrosis (CF) gene has been identified by University of North Carolina (UNC) at Chapel Hill scientists. Turning off the degradation system allows some proteins to regain their proper shape, offering a new avenue for treatments aimed at curing the disease.
The results of this CF study, published August 11, 2006, in the journal Cell, point to several possible targets for the development of new treatments aimed at stopping the disease, the researchers said.
CF is a fatal disease caused by a defective gene that produces a misshapen form of the protein cystic fibrosis transmembrane conductance regulator (CFTR). People with cystic fibrosis do not have enough CFTR for their cells to work normally because their bodies quickly destroy the mutant protein.
To better understand how to fix CFTR, the researchers at the UNC Cystic Fibrosis Pulmonary Research and Treatment Center focused on identifying the cellular system that disposes of faulty CFTR. The investigators identified cell components that specifically recognizes misshapen CFTR and drops it in the molecular “trash bin.” The team found that turning off these components—the cell’s trash collectors—extends the life of faulty CFTR proteins and thereby enables some of it to assume a functional shape.
The trash collectors newly identified by the researchers are two different ubiquitin ligases, proteins that specifically recognize misshaped regions of CFTR and tag them with a degradation signal known as ubiquitin. The ubiquitin tag tells the cell to destroy the marked CFTR, a process overseen by a destroyer called the proteasome. This trash system is known as the ubiquitin proteasome pathway.
“Understanding this pathway gives us greater insight into what’s wrong with the protein—information that will help people design better therapeutics for the disease,” said senior author Douglas Cyr, PhD, professor of cell and developmental biology at UNC School of Medicine.