Abstract
Intestinal epithelial cells (IEC) have important functions in nutrient absorption, barrier integrity, regeneration, pathogen-sensing, and mucus secretion. Goblet cells are a specialized cell type of IEC that secrete Trefoil factor 3 (TFF3) to regulate mucus viscosity and wound healing, but whether TFF3-responsiveness requires a receptor is unclear. Here, we show that leucine rich repeat receptor and nogo-interacting protein 2 (LINGO2) is essential for TFF3-mediated functions. LINGO2 immunoprecipitates with TFF3, co-localizes with TFF3 on the cell membrane of IEC, and allows TFF3 to block apoptosis. We further show that TFF3-LINGO2 interactions disrupt EGFR-LINGO2 complexes resulting in enhanced EGFR signaling. Excessive basal EGFR activation in Lingo2 deficient mice increases disease severity during colitis and augments immunity against helminth infection. Conversely, TFF3 deficiency reduces helminth immunity. Thus, TFF3-LINGO2 interactions de-repress inhibitory LINGO2-EGFR complexes, allowing TFF3 to drive wound healing and immunity.
Highlights
Intestinal epithelial cells (IEC) have important functions in nutrient absorption, barrier integrity, regeneration, pathogen-sensing, and mucus secretion
We postulated that Trefoil factor 3 (TFF3) interacted with its receptor through low-affinity interactions reliant upon carbohydrates because TFF3 glycosylation has been shown critical for biological activity[34,35], U937 cells were subjected to the TRICEPSTM protocol as a biochemical screening strategy to identify glycosylated transmembrane protein(s) on the cell surface[32,36]
RhTFF3 was covalently linked to the TRICEPS probe and incubated with PMA-treated U937 that had been treated with sodium periodate
Summary
Intestinal epithelial cells (IEC) have important functions in nutrient absorption, barrier integrity, regeneration, pathogen-sensing, and mucus secretion. LINGO2 deficiency in mice results in a phenotype opposite of TFF3 deficiency due to repressive EGFR-LINGO2 interactions In support of this hypothesis, the increased disease severity of DSS colitis in LINGO2 deficient mice and their resistance to N.b. infection is both reversed following treatment with the EGFR antagonist Gefitinib. Taken together, these data suggest a model wherein TFF3 binding to LINGO2 reverses tonic inhibition of EGFR by LINGO2, resulting in heightened EGFR activation
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