TFF3 interacts with LINGO2 to regulate EGFR activation for protection against colitis and gastrointestinal helminths
TFF3 interacts with LINGO2 to regulate EGFR activation for protection against colitis and gastrointestinal helminths
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DOI：
10.1038/s41467-019-12315-1
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发表时间：
2019-09-27
影响因子：
16.6
通讯作者：
Herbert, De'Broski R.
中科院分区：
文献类型：
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作者：
Belle, Nicole Maloney;Ji, Yingbiao;Herbert, De'Broski R.
肠上皮细胞（IEC）在营养吸收、屏障完整性、再生、病原体感应和粘液分泌方面具有重要功能。杯状细胞是IEC的一种特化细胞类型，其分泌三叶因子3（TFF 3）以调节粘液粘度和伤口愈合，但TFF 3反应性是否需要受体尚不清楚。在这里，我们表明，亮氨酸丰富的重复受体和nogo相互作用蛋白2（LINGO 2）是必不可少的TFF 3介导的功能。LINGO 2与TFF 3免疫沉淀，与TFF 3共定位在IEC的细胞膜上，并允许TFF 3阻断细胞凋亡。我们进一步表明，TFF 3-LINGO 2相互作用破坏EGFR-LINGO 2复合物，导致增强的EGFR信号传导。Lingo 2缺陷小鼠中过度的基础EGFR激活增加了结肠炎期间的疾病严重程度，并增强了对蠕虫感染的免疫力。相反，TFF 3缺乏会降低蠕虫免疫力。因此，TFF 3-LINGO 2相互作用解除抑制性LINGO 2-EGFR复合物的抑制，使TFF 3能够驱动伤口愈合和免疫。
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.