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

Mol Cells. 2015 May;38(5):441-51. doi: 10.14348/molcells.2015.2359. Epub 2015 May 7.

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; JAK1-STAT1 signaling; SHP-1/2; Stimulator of interferon genes protein; double-stranded DNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • B-Lymphocytes / metabolism*
  • DNA / metabolism*
  • Female
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Janus Kinase 1 / metabolism
  • Jurkat Cells
  • Lupus Erythematosus, Systemic / immunology*
  • Male
  • Membrane Proteins / metabolism*
  • Mice
  • Phosphorylation
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / metabolism*
  • STAT1 Transcription Factor / metabolism
  • Signal Transduction
  • Spleen / immunology

Substances

  • MPYS protein, mouse
  • Membrane Proteins
  • STAT1 Transcription Factor
  • STING protein, human
  • DNA
  • Janus Kinase 1
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6