TFF3 interacts with LINGO2 to regulate EGFR activation for protection against colitis and gastrointestinal helminths

Nicole Maloney Belle, Yingbiao Ji, Karl Herbine, Yun Wei, JoonHyung Park, Kelly Zullo, Li-Yin Hung, Sriram Srivatsa, Tanner Young, Taylor Oniskey, Christopher Pastore, Wildaliz Nieves, Ma Somsouk and Herbert De’Broski R. ()
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Nicole Maloney Belle: University of Pennsylvania School of Veterinary Medicine
Yingbiao Ji: University of Pennsylvania School of Veterinary Medicine
Karl Herbine: University of Pennsylvania School of Veterinary Medicine
Yun Wei: University of California, San Francisco
JoonHyung Park: University of Pennsylvania School of Veterinary Medicine
Kelly Zullo: University of Pennsylvania School of Veterinary Medicine
Li-Yin Hung: University of Pennsylvania School of Veterinary Medicine
Sriram Srivatsa: University of Pennsylvania School of Veterinary Medicine
Tanner Young: University of Pennsylvania School of Veterinary Medicine
Taylor Oniskey: University of California, San Francisco
Christopher Pastore: University of Pennsylvania School of Veterinary Medicine
Wildaliz Nieves: University of California, San Francisco
Ma Somsouk: University of California, San Francisco
Herbert De’Broski R.: University of Pennsylvania School of Veterinary Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-12315-1

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