Cell surface IL-1α trafficking is specifically inhibited by interferon-γ, and associates with the membrane via IL-1R2 and GPI anchors
Cell surface IL-1α trafficking is specifically inhibited by interferon-γ, and associates with the membrane via IL-1R2 and GPI anchors
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DOI：
10.1002/eji.201948521
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发表时间：
2020-06-08
影响因子：
5.4
通讯作者：
Clarke, Murray C. H.
中科院分区：
文献类型：
--
作者：
Chan, Julie N. E.;Humphry, Melanie;Clarke, Murray C. H.
IL-1是一种强大的细胞因子，可以驱动炎症和调节获得性免疫。IL-1α和IL-1β都被翻译为需要切割才能充分激活和释放细胞因子的形式，而IL-1α被报道为许多细胞类型上的另一种质膜相关形式。然而，细胞表面IL-1α(CSIL-1α)的存在是有争议的，IL-1α是如何拴在细胞膜上的尚不清楚，控制运输的信号通路也没有具体说明。使用一个强大的和充分验证的系统，我们证明了巨噬细胞在结扎TLRs后呈现真正的CSIL-1α。Pro-IL-1α部分通过IL-1R2或通过与糖基磷脂酰肌醇锚定蛋白结合与质膜结合，可被蛋白酶切割、激活和释放。CSIL-1α需要从头合成蛋白质，其向质膜的转运对干扰素-γ的抑制非常敏感，与表达水平无关。我们还揭示了先前的CSIL-1α检测是如何通过无意的细胞通透性发生的，并且衰老细胞并不是通过CSIL-1α而是通过可溶性IL-1α来驱动衰老相关的分泌表型。我们认为这些数据对于确定IL-1α在疾病和/或生理过程中的局部或全身性环境是重要的。
IL-1 is a powerful cytokine that drives inflammation and modulates adaptive immunity. Both IL-1 alpha and IL-1 beta are translated as proforms that require cleavage for full cytokine activity and release, while IL-1 alpha is reported to occur as an alternative plasma membrane-associated form on many cell types. However, the existence of cell surface IL-1 alpha (csIL-1 alpha) is contested, how IL-1 alpha tethers to the membrane is unknown, and signaling pathways controlling trafficking are not specified. Using a robust and fully validated system, we show that macrophages present bona fide csIL-1 alpha after ligation of TLRs. Pro-IL-1 alpha tethers to the plasma membrane in part through IL-1R2 or via association with a glycosylphosphatidylinositol-anchored protein, and can be cleaved, activated, and released by proteases. csIL-1 alpha requires de novo protein synthesis and its trafficking to the plasma membrane is exquisitely sensitive to inhibition by IFN-gamma, independent of expression level. We also reveal how prior csIL-1 alpha detection could occur through inadvertent cell permeabilisation, and that senescent cells do not drive the senescent-associated secretory phenotype via csIL-1 alpha, but rather via soluble IL-1 alpha. We believe these data are important for determining the local or systemic context in which IL-1 alpha can contribute to disease and/or physiological processes.