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-beta production. SHP-2 inhibited TLR3-activated but not TLR2-, TLR7-, and TLR9-activated proinflammatory cytokine IL-6 and TNF-alpha 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-beta and TNF-alpha 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.
An
Huazhang
H
Institute of Immunology and National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai 200433, People's Republic of China.
Zhao
Wei
W
Hou
Jin
J
Zhang
Yan
Y
Xie
Yun
Y
Zheng
Yuejuan
Y
Xu
Hongmei
H
Qian
Cheng
C
Zhou
Jun
J
Yu
Yizhi
Y
Liu
Shuxun
S
Feng
Gensheng
G
Cao
Xuetao
X
D033942:Adaptor Proteins, Vesicular Transport / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis* / Q000276:immunology; D005260:Female; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000276:immunology; D015151:Immunoblotting; D007370:Interferon Type I / Q000096:biosynthesis* / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D054648:Protein Phosphatase 2; D017346:Protein Serine-Threonine Kinases / Q000276:immunology / Q000378:metabolism; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000276:immunology / Q000378:metabolism*; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000276:immunology*; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
D033942:Adaptor Proteins, Vesicular Transport; D016207:Cytokines; D007370:Interferon Type I; D054648:Protein Phosphatase 2; D017346:Protein Serine-Threonine Kinases; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D034741:RNA, Small Interfering; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; C476286:Ticam1 protein, mouse; C498588:Tbk1 protein, mouse