二军大、清华、浙大联手发《Immunity》文章

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.