How Trefoil Proteins Act to Thicken Mucus Detailed in Study

Researchers identified a biochemical mechanism that regulates the thickness of mucus, and could serve as a target of new treatments for chronic respiratory illnesses that include cystic fibrosis (CF).

The study, “Trefoil factors share a lectin activity that defines their role in mucus,” was published in the journal Nature Communications.

Difficulties with breathing in such illnesses as CF, asthma, and chronic obstructive pulmonary disease (COPD) are partly attributed to the production of excessive and thicker-than-normal mucus.

Scientists at the Walter + Eliza Hall Institute for Medical Research in Australia wanted to better understand how mucus thickness is regulated in the body.

Mucus itself is a mixture of water and mucin glycoproteins, long strands of protein that are coated with sugar molecules called glycans.

Another protein, called trefoil factors (TFFs), is able to bind to the unique arrangement of glycan sugars in mucin glycoproteins.

TFFs, which come in three types (TFF1, TFF2, and TFF3), are designed to protect the mucosal epithelium by making mucus thicker. Thickening of mucus is necessary to trap potential threats — like dust, dead cells, and bacteria — before they enter the lungs.

However, TFFs are typically overexpressed in people with respiratory illness, creating an overly thick mucus that causes its own problems. This makes TFFs an attractive target for therapies addressing symptoms of respiratory illness.

“Trefoil factors have long been known to make mucus more viscous (thicker), and it has been postulated that this thickening occurs in respiratory diseases,” Ethan Goddard-Borger, PhD, the lead author of the study, said in a press release. “However, until now we did not completely understand how the trefoil factor proteins achieved this.”

Using lab techniques to evaluate binding interactions and atomic structures, researchers identified a specific glycan pattern that is required for all three TFFs to bind.

Researchers also saw that each TFF has two glycan binding sites, allowing them to link two mucin strands together to thicken mucus.

“Within mucus, trefoil factors essentially ‘staple’ the mucin strands into a mesh: the more staples, the denser the mesh and the thicker the mucus becomes,” Goddard-Borger said.

The team is now exploring this newly uncovered mechanism between trefoil factors and mucin strands, looking to create ways to reduce mucus thickness.

“We are seeking to develop innovative approaches for reducing the viscosity of the mucus to aid in clearing excess mucus from the lungs of patients with chronic respiratory disease,” Goddard-Borger said.

The scientists also plan “to work with commercial collaborators to progress our vision to develop new mucolytic drugs [medicines that thin mucus] that can more effectively clear mucus from the airways,” he added.