Researchers are finding hundreds of new proteins that could affect cystic fibrosis

Variety of membrane protein structure.

Researchers at the University of Toronto have identified hundreds of new proteins that may play a role in cystic fibrosis, and that may shed light on why some patients respond better than others to modern treatments.

Many of these proteins – part of a group of drug molecules called membrane proteins – interact with the CFTR protein, which in the absence or malfunction leads to accumulation of mucus in the lungs and other organs, often fatal in cystic fibrosis.

“We have identified more than 400 proteins associated with both healthy and mutant CFTRs, and have shown that some of them can predict the variability of patient symptoms and responses to treatment,” said Igor Staglar, principal investigator and professor at Donnelly. Center for Cellular and Biomolecular Research at the Temerti School of Medicine U.T.

“With a better understanding of the CFTR protein interaction network, we can identify new targets for drugs that should allow for more specific therapy for patients,” Staglar said.

Magazine Molecular Systems Biology published the results today (February 14, 2022) and published them on the cover of the February issue.

Igor Staglyar

Professor Igor Staglyar. Credit: Photo by John McGraw

To help detect the interaction of protein and protein involving CFTR, the researchers developed a new technology based on the platform they developed in 2014. The approach is a high-performance version of their two-hybrid Mammalian Membrane Two-Hybrid system that allows for the screening of many others. membrane proteins that bind to a specific protein.

“The previous design was based on arrays, and we could only view about 200 proteins at a time,” said Staglar, who is also a professor of biochemistry and molecular genetics at U of T. “With this new technology, we’ve introduced several changes that allow us to combine thousands of protein targets at once. ”

Staglar and his lab used technology to find several missing proteins, including many membrane proteins that may play a role in CFTR function and cystic fibrosis. Membrane proteins make up about one-third of all proteins in cells and about 65 percent of all drug therapy targets.

One particularly promising candidate that the team has identified is fibrinogen-like protein 2, which is thought to play a role in hepatitis, liver disease and immune function. Decreased regulation of this protein, the team showed, leads to increased expression of CFTR in organelles – 3D in vitro models showing how cells interact in the body, in this case with intestinal tissues obtained by the patient.

“We believe that a protein similar to fibrinogen 2 is a valuable target for cystic fibrosis drugs, and we are now working with our staff to confirm other proteins found in this study and in association-wide association studies,” he said. Staglar.

Cystic fibrosis affects more than 90,000 people worldwide. The disease can occur when children inherit two mutated CFTR genes, one from each parent, leaving defective CFTR proteins on the cell surface in the lungs and other organs.

About 2,000 known mutations in the CFTR gene can cause disease, and drug treatments are often tailored to each patient’s genetic profile. Some of these treatments have shown remarkable success in the last decade, restoring CFTR protein function. But the response to treatment can vary greatly, even among patients who have the same mutation.

Staglar said that while researchers have long suspected that these changes in response to treatment depend on secondary genetic modifiers and environmental factors, current research strongly suggests that proteins physically associated with CFTR are one of these factors.

Two members of the Stagljar laboratory were among the first authors of the article. Dr. San Hyun Lim, a doctoral student in biochemistry at the time of the study, who is now a graduate student at Genentech, and senior researcher Dr. Jamie Snyder.

Staglar said both have played an important role in the study and show that the university continues to study and enjoy great research talent. Both worked closely with other laboratories on the project, in particular at U of T, The Hospital for Sick Children and the University of Lisbon in Portugal.

“This study represents a breakthrough in proteomics and cystic fibrosis, but it would have been impossible without our many staff,” Staglar said. “We’ve developed technology, but we’re not experts in cystic fibrosis, physiology and other areas, so we’ve teamed up with the best, and they’ve done it – that’s how science works today.”

Reference: “Interactive mapping of CFTR using a two-hybrid high-throughput mammalian membrane screening system” Sang Hyun Lim, Jamie Snyder, Lyron Birimberg-Schwartz, Van Yip, Joanna Si Serralla, Hugo M. Batello, Mikeas Paphos Lopez , Mara Ziloki, Anafria Laselva, Mohsen Esmaeli, Max Kotlyar, Anna Lakisheva, Priscilla Tang, Lucia Lopez Vazquez, Indira Shark, Farzane Abualizade, Victoria Wong, Tehrid Opadi Grozov, Tengrid Ipadia Ghoza Gobuza , Christine E. Bear, Margarida D. Amaral and Igor Staglar, February 14, 2022, Molecular Systems Biology.
DOI: 10.15252 / msb.202110629 Researchers are finding hundreds of new proteins that could affect cystic fibrosis

Back to top button