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

• Published in: Nature communications 2019-09, Vol.10 (1), p.4408-13, Article 4408
• Main Authors: Belle, Nicole Maloney, Ji, Yingbiao, Herbine, Karl, Wei, Yun, Park, JoonHyung, Zullo, Kelly, Hung, Li-Yin, Srivatsa, Sriram, Young, Tanner, Oniskey, Taylor, Pastore, Christopher, Nieves, Wildaliz, Somsouk, Ma, Herbert, De’Broski R.
• Format: Article
• Language: English
• Subjects: 13/21; 13/31; 13/95; 631/250/255/1715; 631/250/256/2515; 631/80/304; 631/80/86/2368; 64/110; 82/1; 82/51; Activation; Animals; Apoptosis; Cell Line, Tumor; Cell membranes; Colitis; Colitis - chemically induced; Colitis - immunology; Colitis - metabolism; Dextran Sulfate; Epidermal growth factor receptors; Epithelial cells; ErbB Receptors - genetics; ErbB Receptors - immunology; ErbB Receptors - metabolism; Goblet cells; Goblet Cells - immunology; Goblet Cells - metabolism; Goblet Cells - parasitology; HEK293 Cells; Helminthiasis - immunology; Helminthiasis - metabolism; Helminthiasis - parasitology; Helminths - immunology; Helminths - physiology; Humanities and Social Sciences; Humans; Immunity; Inflammatory bowel disease; Intestinal Mucosa - immunology; Intestinal Mucosa - metabolism; Intestinal Mucosa - parasitology; Intestine; Leucine; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice, Inbred C57BL; Mucus; multidisciplinary; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - immunology; Nerve Tissue Proteins - metabolism; Nogo protein; Organophosphonates; Regeneration; Science; Science (multidisciplinary); Trefoil factor; Trefoil Factor-3 - genetics; Trefoil Factor-3 - immunology; Trefoil Factor-3 - metabolism; U937 Cells; Viscosity; Wound healing
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-12315-1

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. TFF3 secretion by goblet cells regulates mucus viscosity and wound healing, but a receptor for TFF3 has not been identified. Here, the authors show that TFF3 binds LINGO2 to de-repress and enhance EGFR signaling that drives wound healing and immunity against helminths.