Membrane Traffic Lab, Instituto Gulbenkian de Ciência, Oeiras, Portugal.
Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College Dublin, Dublin, Ireland.
Elife. 2018 Jun 13;7:e35032. doi: 10.7554/eLife.35032.
The apical inflammatory cytokine TNF regulates numerous important biological processes including inflammation and cell death, and drives inflammatory diseases. TNF secretion requires TACE (also called ADAM17), which cleaves TNF from its transmembrane tether. The trafficking of TACE to the cell surface, and stimulation of its proteolytic activity, depends on membrane proteins, called iRhoms. To delineate how the TNF/TACE/iRhom axis is regulated, we performed an immunoprecipitation/mass spectrometry screen to identify iRhom-binding proteins. This identified a novel protein, that we name iTAP (iRhom Tail-Associated Protein) that binds to iRhoms, enhancing the cell surface stability of iRhoms and TACE, preventing their degradation in lysosomes. Depleting iTAP in primary human macrophages profoundly impaired TNF production and tissues from iTAP KO mice exhibit a pronounced depletion in active TACE levels. Our work identifies iTAP as a physiological regulator of TNF signalling and a novel target for the control of inflammation.
顶端炎症细胞因子 TNF 调节许多重要的生物学过程，包括炎症和细胞死亡，并导致炎症性疾病。TNF 的分泌需要 TACE（也称为 ADAM17），它将 TNF 从其跨膜系绳中切割下来。TACE 向细胞表面的运输以及其蛋白水解活性的刺激取决于膜蛋白，称为 iRhoms。为了描绘 TNF/TACE/iRhom 轴是如何被调节的，我们进行了免疫沉淀/质谱筛选以鉴定 iRhom 结合蛋白。这鉴定出一种新型蛋白，我们将其命名为 iTAP（iRhom 尾部相关蛋白），它与 iRhoms 结合，增强 iRhoms 和 TACE 的细胞表面稳定性，防止它们在溶酶体中降解。在原代人巨噬细胞中耗尽 iTAP 会严重损害 TNF 的产生，而 iTAP KO 小鼠的组织中活性 TACE 水平明显下降。我们的工作确定了 iTAP 是 TNF 信号的生理调节剂，也是控制炎症的新靶点。
