Trefoil factors share a lectin activity that defines their role in mucus

Abstract

The mucosal epithelium secretes a host of protective disulfide-rich peptides, including the trefoil factors (TFFs). The TFFs increase the viscoelasticity of the mucosa and promote cell migration, though the molecular mechanisms underlying these functions have remained poorly defined. Here, we demonstrate that all TFFs are divalent lectins that recognise the GlcNAc-α-1,4-Gal disaccharide, which terminates some mucin-like O-glycans. Degradation of this disaccharide by a glycoside hydrolase abrogates TFF binding to mucins. Structural, mutagenic and biophysical data provide insights into how the TFFs recognise this disaccharide and rationalise their ability to modulate the physical properties of mucus across different pH ranges. These data reveal that TFF activity is dependent on the glycosylation state of mucosal glycoproteins and alludes to a lectin function for trefoil domains in other human proteins.

Trefoil Factor Family (TFF) Peptides and Their Links to Inflammation: A Re-evaluation and New Medical Perspectives

“…This concentration is atypical of classical receptor/peptide ligand interactions and is in agreement with a failure to detect high-affinity TFF binding proteins [ 21 ]. Thus, rather low-affinity binding can be expected, which would be in agreement with the known, but different, lectin activities of TFF peptides [ 4 , 22 ]. Such a hypothetical function of TFF peptides as activating lectin ligands for a plethora of transmembrane glycoproteins triggering signal transduction processes has already been proposed in the past [ 23 ].…”

“…Here, they play a role as a gastric tumor suppressor (TFF1) or they are involved in the mucosal innate immune defense as integral parts of the mucus barrier (TFF2/MUC6 lectin complex, TFF3-FCGBP heterodimer) [ 4 , 20 ]. As a hallmark, all three TFF peptides have lectin activities, best characterized for TFF2 [ 4 , 22 ]. Thus, TFF peptides as soluble lectins are comparable with multifunctional galectins and C-type lectins, which also interact with mucins [ 172 , 173 ].…”

Effects of Environmental Factors on Severity and Mortality of COVID-19

“…Mucin glycans mimic cell surface glycosylation and, by acting as a decoy for viral lectins, trap viral particles, which are then transported out of airways by mucociliary clearance (24). Furthermore, since all envelope viruses are highly glycosylated, a number of lectins like trefoil factors (TFF) are secreted to mucous where they crosslink viruses by binding to glycans on both viruses and mucins (25). However, this barrier is functional only if it is well hydrated to both maintain its structural integrity and enable constant flow of mucus that remove viruses and other pathogens from our airways (24).…”

Pretreatment with intestinal trefoil factor alleviates stress-induced gastric mucosal damage via Akt signaling

“…Additionally, the TFFs, including ITF, are reported to share a divalent lectin activity that recognizes the N-acetylglucosamine-α-1, 4-galactose disaccharide and interact with mucosal glycoproteins relying on the glycosylation state. How their lectin activities might promote cell migration to achieve epithelial restitution remains unclear[ 32 ]. Accumulating evidence has implicated glycosylation as an underappreciated post-translational modification, and glycan alterations have an important impact on the mucus layer, glycan–lectin interactions, and mucosal immunity[ 32 - 34 ].…”