Interleukin-2 signalling is modulated by a labile disulfide bond in the CD132 chain of its receptor.
Interleukin-2 signalling is modulated by a labile disulfide bond in the CD132 chain of its receptor.
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DOI：
10.1098/rsob.110036
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发表时间：
2012-01
期刊：
影响因子：
5.8
通讯作者：
Barclay AN
中科院分区：
文献类型：
--
作者：
Metcalfe C;Cresswell P;Barclay AN
白细胞膜蛋白中存在的某些二硫键不稳定，在炎症中可能会减少。这可能会导致结构变化，从而导致下游功能效应，例如整合素激活。最近的研究表明，多种膜蛋白具有不稳定的二硫键，包括 CD132，它是多种细胞因子（包括白细胞介素 2 和白细胞介素 4（IL-2 和 IL-4））受体的常见 γ 链。小鼠 CD132 中的 Cys183-Cys232 二硫键容易被硫氧还蛋白 (TRX)、γ 干扰素诱导的溶酶体硫醇还原酶和蛋白质二硫键异构酶等酶还原，这些酶通常在免疫激活过程中分泌。在体内脂多糖 (LPS) 诱导的急性炎症模型中，Cys183–Cys232 二硫键也减少。导致 CD132 中 Cys183-Cys232 二硫键减少的条件会抑制 IL-2 依赖性 T 细胞克隆的增殖，并同时抑制 STAT-5 信号通路。相同的还原条件对不依赖 IL-2 的 T 细胞克隆的增殖没有影响，也不会还原 IL-2 本身的二硫键。我们假设 CD132 中 Cys183-Cys232 二硫键的还原会抑制 IL-2 与受体复合物的结合。已发表的数据显示，Cys183-Cys232二硫键暴露在CD132表面，并与各自受体复合物中的IL-2和IL-4紧密接触。此外，人 CD132 中这些 Cys 残基的突变会导致免疫缺陷和 IL-2 结合丧失。这些结果对细胞因子受体的调节具有更广泛的影响，因为它们的活性可以通过炎症和免疫系统激活期间发生的氧化还原环境变化引起的“氧化还原调节剂”机制来调节。
Certain disulfide bonds present in leucocyte membrane proteins are labile and can be reduced in inflammation. This can cause structural changes that result in downstream functional effects, for example, in integrin activation. Recent studies have shown that a wide range of membrane proteins have labile disulfide bonds including CD132, the common gamma chain of the receptors for several cytokines including interleukin-2 and interleukin-4 (IL-2 and IL-4). The Cys183–Cys232 disulfide bond in mouse CD132 is susceptible to reduction by enzymes such as thioredoxin (TRX), gamma interferon-inducible lysosomal thiolreductase and protein disulfide isomerase, which are commonly secreted during immune activation. The Cys183–Cys232 disulfide bond is also reduced in an in vivo lipopolysaccharide (LPS)-induced acute model of inflammation. Conditions that lead to the reduction of the Cys183–Cys232 disulfide bond in CD132 inhibit proliferation of an IL-2-dependent T cell clone and concomitant inhibition of the STAT-5 signalling pathway. The same reducing conditions had no effect on the proliferation of an IL-2-independent T cell clone, nor did they reduce disulfide bonds in IL-2 itself. We postulate that reduction of the Cys183–Cys232 disulfide in CD132 inhibits IL-2 binding to the receptor complex. Published data show that the Cys183–Cys232 disulfide bond is exposed at the surface of CD132 and in close contact with IL-2 and IL-4 in their respective receptor complexes. In addition, mutants in these Cys residues in human CD132 lead to immunodeficiency and loss of IL-2 binding. These results have wider implications for the regulation of cytokine receptors in general, as their activity can be modulated by a ‘redox regulator’ mechanism caused by the changes in the redox environment that occur during inflammation and activation of the immune system.
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影响因子：
4.8
作者：
Mor-Cohen, Ronit;Rosenberg, Nurit;Seligsohn, Uri
通讯作者：
Seligsohn, Uri
影响因子：
8.6
作者：
Niemela, JE;Puck, JM;Hsu, AP
通讯作者：
Hsu, AP
影响因子：
64.8
作者：
Schroeder, Bjoern O.;Wu, Zhihong;Wehkamp, Jan
通讯作者：
Wehkamp, Jan
DOI：
10.1073/pnas.2434516100
发表时间：
2003-12-09
影响因子：
11.1
作者：
Laragione, T;Bonetto, V;Ghezzi, P
通讯作者：
Ghezzi, P
DOI：
10.1073/pnas.0604571103
发表时间：
2006-08-22
影响因子：
11.1
作者：
Gelderman, Kyra A.;Hultqvist, Malin;Holmdahl, Rikard
通讯作者：
Holmdahl, Rikard