Molecular Immunology Unit, Institute for Hygiene and Applied Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, Austria;
J Immunol. 2014 Jan 15;192(2):771-81. doi: 10.4049/jimmunol.1300377. Epub 2013 Dec 13.
GTPases act as important switches in many signaling events in cells. Although small and heterotrimeric G proteins are subjects of intensive studies, little is known about the large IFN-inducible GTPases. In this article, we show that the IFN-γ-inducible guanylate binding protein 1 (GBP-1) is a regulator of T cell activation. Silencing of GBP-1 leads to enhanced activation of early T cell Ag receptor/CD3 signaling molecules, including Lck, that is translated to higher IL-2 production. Mass spectrometry analyses showed that regulatory cytoskeletal proteins, like plastin-2 that bundles actin fibers and spectrin β-chain, brain 1 that links the plasma membrane to the actin cytoskeleton, are binding partners of GBP-1. The spectrin cytoskeleton influences cell spreading and surface expression of TCR/CD3 and the leukocyte phosphatase CD45. We found higher cell spreading and enhanced surface expression of TCR/CD3 and CD45 in GBP-1 silenced T cells that explain their enhanced TCR/CD3 signaling. We conclude that GBP-1 is a downstream processor of IFN-γ via which T cells regulate cytoskeleton-dependent cell functions.
G 蛋白家族在细胞内的许多信号转导事件中充当着重要的开关。尽管小分子异三聚体 G 蛋白是密集研究的对象，但人们对大的 IFN 诱导的 GTP 酶知之甚少。在本文中，我们表明 IFN-γ 诱导的鸟嘌呤核苷酸结合蛋白 1（GBP-1）是 T 细胞激活的调节剂。沉默 GBP-1 会导致早期 T 细胞抗原受体/CD3 信号分子（包括 Lck）的激活增强，这会转化为更高水平的 IL-2 产生。质谱分析表明，调节细胞骨架的蛋白质，如成束肌动蛋白纤维的 plastin-2 和连接质膜与肌动蛋白细胞骨架的 spectrin β 链，是 GBP-1 的结合伙伴。 spectrin 细胞骨架影响 TCR/CD3 和白细胞磷酸酶 CD45 的细胞铺展和表面表达。我们发现，沉默 GBP-1 的 T 细胞的细胞铺展增加，TCR/CD3 和 CD45 的表面表达增强，这解释了它们增强的 TCR/CD3 信号。我们的结论是，GBP-1 是 IFN-γ 的下游处理器，通过它 T 细胞调节细胞骨架依赖性的细胞功能。
