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; De'Broski R Herbert

doi:10.1038/s41467-019-12315-1

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

Nat Commun. 2019 Sep 27;10(1):4408. doi: 10.1038/s41467-019-12315-1.

Authors

Nicole Maloney Belle¹, Yingbiao Ji¹, Karl Herbine¹, Yun Wei^{2

3}, JoonHyung Park¹, Kelly Zullo¹, Li-Yin Hung^{1

2}, Sriram Srivatsa¹, Tanner Young¹, Taylor Oniskey², Christopher Pastore¹, Wildaliz Nieves⁴, Ma Somsouk⁴, De'Broski R Herbert^{5

6}

Affiliations

¹ Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, 19140, USA.
² Division of Experimental Medicine, University of California, San Francisco, San Francisco, CA, 94110, USA.
³ Department of Inflammation and Oncology, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA, 94080, USA.
⁴ Division of Gastroenterology at ZSFG, University of California, San Francisco, San Francisco, CA, 94110, USA.
⁵ Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, 19140, USA. debroski@vet.upenn.edu.
⁶ Division of Experimental Medicine, University of California, San Francisco, San Francisco, CA, 94110, USA. debroski@vet.upenn.edu.

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.

MeSH terms

Animals
Cell Line, Tumor
Colitis / chemically induced
Colitis / immunology*
Colitis / metabolism
Dextran Sulfate
ErbB Receptors / genetics
ErbB Receptors / immunology*
ErbB Receptors / metabolism
Goblet Cells / immunology
Goblet Cells / metabolism
Goblet Cells / parasitology
HEK293 Cells
Helminthiasis / immunology*
Helminthiasis / metabolism
Helminthiasis / parasitology
Helminths / immunology
Helminths / physiology
Humans
Intestinal Mucosa / immunology*
Intestinal Mucosa / metabolism
Intestinal Mucosa / parasitology
Membrane Proteins / genetics
Membrane Proteins / metabolism*
Mice, Inbred C57BL
Nerve Tissue Proteins / genetics
Nerve Tissue Proteins / immunology*
Nerve Tissue Proteins / metabolism
Organophosphonates
Trefoil Factor-3 / genetics
Trefoil Factor-3 / immunology*
Trefoil Factor-3 / metabolism
U937 Cells

Substances

Lingo2 protein, mouse
Membrane Proteins
Nerve Tissue Proteins
Organophosphonates
Tff3 protein, mouse
Trefoil Factor-3
(2-(dimethylamino)ethyl)phosphonic acid
Dextran Sulfate
EGFR protein, mouse
ErbB Receptors

Abstract

MeSH terms

Substances

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