Functional Expression of the P2X7 ATP Receptor Requires Eros
Functional Expression of the P2X7 ATP Receptor Requires Eros
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DOI：
10.4049/jimmunol.1900448
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发表时间：
2020-02-01
影响因子：
4.4
通讯作者：
Nagata, Shigekazu
中科院分区：
文献类型：
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作者：
Ryoden, Yuta;Fujii, Toshihiro;Nagata, Shigekazu
响应于细胞外ATP，嘌呤能受体P2 X7介导各种生物过程，包括磷脂酰丝氨酸（PtdSer）暴露、磷脂混杂、染料摄取、离子转运和IL-1 β产生。对负责ATP诱导的PtdSer暴露的分子进行的全基因组CRISPR筛选确定了一种对活性氧（Eros）至关重要的跨膜蛋白，作为P2 X7表达的必要组分。Eros-null小鼠T细胞系丧失了暴露PtdSer、扰乱磷脂以及内化染料YO-PRO-1和Ca 2+离子的能力。Eros无效突变消除了LPS致敏的人THP-1巨噬细胞系和小鼠骨髓源性巨噬细胞响应ATP分泌IL-1 β的能力。Eros定位于内质网，并作为NADPH氧化酶组分的伴侣。类似地，内质网上的Eros与P2 X7短暂相关，以促进P2 X7的稳定同源三聚体复合物的形成。这些结果表明，Eros不仅作为NADPH氧化酶的伴侣，而且还作为P2 X7的伴侣，参与天然免疫反应。
In response to extracellular ATP, the purinergic receptor P2X7 mediates various biological processes, including phosphatidylserine (PtdSer) exposure, phospholipid scrambling, dye uptake, ion transport, and IL-1 beta production. A genome-wide CRISPR screen for molecules responsible for ATP-induced PtdSer exposure identified a transmembrane protein, essential for reactive oxygen species (Eros), as a necessary component for P2X7 expression. An Eros-null mouse T cell line lost the ability to expose PtdSer, to scramble phospholipids, and to internalize a dye YO-PRO-1 and Ca2+ ions. Eros-null mutation abolished the ability of an LPS-primed human THP-1 macrophage cell line and mouse bone marrow-derived macrophages to secrete IL-1 beta in response to ATP. Eros is localized to the endoplasmic reticulum and functions as a chaperone for NADPH oxidase components. Similarly, Eros at the endoplasmic reticulum transiently associated with P2X7 to promote the formation of a stable homotrimeric complex of P2X7. These results indicated that Eros acts as a chaperone not only for NADPH oxidase, but also for P2X7, and contributes to the innate immune reaction.