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http://dx.doi.org/10.14348/molcells.2015.2359

STING Negatively Regulates Double-Stranded DNA-Activated JAK1-STAT1 Signaling via SHP-1/2 in B Cells  

Dong, Guanjun (The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University)
You, Ming (The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University)
Ding, Liang (The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University)
Fan, Hongye (State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University)
Liu, Fei (The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University)
Ren, Deshan (The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University)
Hou, Yayi (The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University)
Publication Information
Molecules and Cells / v.38, no.5, 2015 , pp. 441-451 More about this Journal
Abstract
Recognition of cytosolic DNA initiates a series of innate immune responses by inducing IFN-I production and subsequent triggering JAK1-STAT1 signaling which plays critical roles in the pathogenesis of infection, inflammation and autoimmune diseases through promoting B cell activation and antibody responses. The stimulator of interferon genes protein (STING) has been demonstrated to be a critical hub of type I IFN induction in cytosolic DNA-sensing pathways. However, it still remains unknown whether cytosolic DNA can directly activate the JAK1-STAT1 signaling or not. And the role of STING is also unclear in this response. In the present study, we found that dsDNA directly triggered the JAK1-STAT1 signaling by inducing phosphorylation of the Lyn kinase. Moreover, this response is not dependent on type I IFN receptors. Interestingly, STING could inhibit dsDNA-triggered activation of JAK1-STAT1 signaling by inducing SHP-1 and SHP-2 phosphorylation. In addition, compared with normal B cells, the expression of STING was significantly lower and the phosphorylation level of JAK1 was significantly higher in B cells from MRL/lpr lupus-prone mice, highlighting the close association between STING low-expression and JAK1-STAT1 signaling activation in B cells in autoimmune diseases. Our data provide a molecular insight into the novel role of STING in dsDNA-mediated inflammatory disorders.
Keywords
B cells; double-stranded DNA; JAK1-STAT1 signaling; SHP-1/2; Stimulator of interferon genes protein;
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