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二军大、清华、浙大联手发《Immunity》文章
【字体: 大 中 小 】 时间:2006年12月21日 来源:生物通
编辑推荐:
生物通报道:来自第二军医大学的安华章和赵伟(Wei Zhao,音译)、清华大学张彦(Yan Zhang,音译)以及浙江大学谢云(Yun Xie,音译)等证实SHP-2负向调节TLR3-和TLR4-激活的IFN-β表达。研究结果刊登于12月19日电子版《Immunity》杂志。
生物通报道:TLR3(Toll-like receptor 3 ,Toll样受体3)和TLR4信号途径包括:接头蛋白TRIF激活I型干扰素(IFN)和前炎症细胞因子的表达。调节TRIF途径依赖的基因表达(TRIF pathway-dependent gene expression)机制至今仍不为人知。
含SH2结构域蛋白酪氨酸磷酸酶2(SH2-containing protein tyrosine phosphatase 2 ,SHP-2)是分布广泛的细胞质酪氨酸磷酸酶。
来自第二军医大学的安华章和赵伟(Wei Zhao,音译)、清华大学张彦(Yan Zhang,音译)以及浙江大学谢云(Yun Xie,音译)等证实SHP-2负向调节TLR3-和TLR4-激活的IFN-β表达。研究结果刊登于12月19日电子版《Immunity》杂志。
安华章等发现SHP-2抑制TLR3激活的,但非TLR2-、TLR7-和TLR9-激活的前炎症细胞因子IL-6和TNF-α的表达;SHP-2通过磷酸酶活性依赖机制,抑制poly(I:C)诱导的细胞因子的生产;SHP-2的C-末端直接与TANK结合激酶(TANK binding kinase,TBK1)结合;SHP-2缺失,促进TBK1激活的IFN-β和TNF-α的表达;在SHP-2缺失细胞中,TBK1会下调poly(I:C)诱导的IL-6产物;SHP-2也可以抑制poly(I:C)诱导的MAP激酶途径的激活。
这些现象说明SHP-2通过抑制TBK1活化的信号转导,负向调节TLR信号途径中TRIF介导的基因表达。(生物通记者 小粥)
文章题目:SHP-2 Phosphatase Negatively Regulates the TRIF Adaptor Protein-Dependent Type I Interferon and Proinflammatory Cytokine Production
The Toll-like receptor 3 (TLR3) and TLR4-signaling pathway that involves the adaptor protein TRIF activates type I interferon (IFN) and proinflammatory cytokine expression. Little is known about how TRIF pathway-dependent gene expression is regulated. SH2-containing protein tyrosine phosphatase 2 (SHP-2) is a widely expressed cytoplasmic tyrosine phosphatase. Here we demonstrate that SHP-2 negatively regulated TLR4- and TLR3-activated IFN-β production. SHP-2 inhibited TLR3-activated but not TLR2-, TLR7-, and TLR9-activated proinflammatory cytokine IL-6 and TNF-α production. SHP-2 inhibited poly(I:C)-induced cytokine production by a phosphatase activity-independent mechanism. C-terminal domain of SHP-2 directly bound TANK binding kinase (TBK1) by interacting with the kinase domain of TBK1. SHP-2 deficiency increased TBK1-activated IFN-β and TNF-α expression. TBK1 knockdown inhibited poly(I:C)-induced IL-6 production in SHP-2-deficient cells. SHP-2 also inhibited poly(I:C)-induced activation of MAP kinase pathways. These results demonstrate that SHP-2 specifically negatively regulate TRIF-mediated gene expression in TLR signaling, partially through inhibiting TBK1-activated signal transduction.