title: STING Negatively Regulates Double-Stranded DNA-Activated JAK1-STAT1 Signaling via SHP-1/2 in B Cells.
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.
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, China.
authors.forename: Guanjun
authors.initials: G
authors.lastname: Dong
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, China.
authors.forename: Ming
authors.initials: M
authors.lastname: You
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Ding
authors.affiliation: State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Hongye
authors.initials: H
authors.lastname: Fan
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, China.
authors.forename: Deshan
authors.initials: D
authors.lastname: Ren
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, China.|Jiangsu Key Laboratory of Molecular Medicine, Nanjing 210093, China.
authors.forename: Yayi
authors.initials: Y
authors.lastname: Hou
mesh_terms: D000328:Adult; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D005260:Female; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D053613:Janus Kinase 1 / Q000378:metabolism; D019169:Jurkat Cells; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism*; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013154:Spleen / Q000276:immunology; D000099197:STING Protein
chemical_list: D004247:DNA; D053613:Janus Kinase 1; D008565:Membrane Proteins; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D050794:STAT1 Transcription Factor; C532857:STING1 protein, human; D000099197:STING Protein; C530855:Sting1 protein, mouse
keywords: B cells; JAK1-STAT1 signaling; SHP-1/2; Stimulator of interferon genes protein; double-stranded DNA