Generation and characterization of ecto-ADP-ribosyltransferase ART2.1/ART2.2-deficient mice
Generation and characterization of ecto-ADP-ribosyltransferase ART2.1/ART2.2-deficient mice
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DOI：
10.1128/mcb.22.21.7535-7542.2002
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发表时间：
2002-11-01
影响因子：
5.3
通讯作者：
Koch-Nolte, F
中科院分区：
文献类型：
--
作者：
Ohlrogge, W;Haag, F;Koch-Nolte, F
这是第一项报告小鼠毒素相关胞外 ADP 核糖基转移酶 (ART) 基因家族成员失活的研究。 ADP-核糖部分从 NAD 转移到 T 细胞膜蛋白上的细胞外精氨酸残基上是由糖基磷脂酰肌醇连接的细胞表面 ART 介导的。 T 细胞暴露于 ecto-NAD 会阻止 T 细胞活化并诱导 T 细胞凋亡。为了确定 ecto-ART2.1 和 ART2.2 在这些过程中的可能作用，我们生成了 ART2.1/ART2.2 双敲除小鼠。 ART2缺陷小鼠健康且具有生育能力，并且淋巴器官发育正常。 ART2缺陷的T细胞表现出ADP-核糖基化细胞表面蛋白的能力显着降低，这表明T细胞表面上的大部分（如果不是全部）ART活性可归因于ART2。此外，ART2缺陷的T细胞完全抵抗NAD诱导的细胞凋亡，部分抵抗NAD介导的增殖抑制。这些结果表明，ART2 胞外酶是细胞外 NAD 调节 T 细胞功能的重要组成部分，例如，在组织损伤和炎症中细胞裂解后释放 NAD。
This is the first study reporting the inactivation of a member of the mouse gene family of toxin-related ecto-ADP-ribosyltransferases (ARTs). Transfer of the ADP-ribose moiety from NAD onto extracellular arginine residues on T-cell membrane proteins is mediated by glycosylphosphatidylinositol-linked cell surface ARTs. Exposure of T cells to ecto-NAD blocks T-cell activation and induces T-cell apoptosis. To determine a possible role of ecto-ART2.1 and ART2.2 in these processes, we generated ART2.1/ART2.2 double-knockout mice. ART2-deficient mice were healthy and fertile and showed normal development of lymphoid organs. ART2-deficient T cells showed a dramatically reduced capacity to ADP-ribosylate cell surface proteins, indicating that most if not all ART activity on the T-cell surface can be attributed to the ART2s. Moreover, ART2-deficient T cells were completely resistant to NAD-induced apoptosis and partially resistant to NAD-mediated suppression of proliferation. These results demonstrate that the ART2 ectoenzymes are an essential component in the regulation of T-cell functions by extracellular NAD, e.g., following release of NAD upon lysis of cells in tissue injury and inflammation.