DNA-Mediated Cyclic GMP-AMP Synthase-Dependent and -Independent Regulation of Innate Immune Responses.

Abstract

Cytoplasmic DNA activates cyclic GMP-AMP synthase (cGAS) to produce cyclic 2'-5'3'-5'GMP-AMP dinucleotide (2'5 'cGAMP). The binding of 2'5'cGAMP to an adaptor protein, stimulator of IFN genes (STING), activates a transcription factor, IFN regulatory factor 3, leading to the induction of IFN and chemokine gene expression. In this study, we found that the 2'5'cGAMP-dependent STING activation induced highly upregulated CXCL10 gene expression. Formation of a distinct STING dimer, which was detected by native PAGE, was induced by 2'5'cGAMP, but not 3'-5'3'-5'cGAMP. Analysis of DNase II(-/-) mice, which constitutively produce IFN-β and CXCL10, showed the accumulation of 2'5'cGAMP in their fetal livers and spleens, suggesting that the undigested DNA accumulating in DNase II(-/-) cells may have leaked from the lysosomes into the cytoplasm. The DNase II(-/-) mouse embryonic fibroblasts produced 2'5'cGAMP in a cGAS-dependent manner during apoptotic cell engulfment. However, cGAS deficiency did not impair the STING-dependent upregulation of CXCL10 in DNase II(-/-) mouse embryonic fibroblasts that was induced by apoptotic cell engulfment or DNA lipofection. These results suggest the involvement of a cGAS-independent additional DNA sensor(s) that induces the STING-dependent activation of innate immunity.

• Authors: Kou Motani, Shinji Ito, Shigekazu Nagata
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 194 Issue 10 Pg. 4914-23 (May 15 2015) ISSN: 1550-6606 [Electronic] United States
• PMID: 25855353 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 by The American Association of Immunologists, Inc.

Chemical References

• Membrane Proteins
• Sting1 protein, mouse
• DNA
• Nucleotidyltransferases
• cGAS protein, mouse

Topics

• Animals
• Cells, Cultured
• DNA (immunology)
• Immunity, Innate (immunology)
• Membrane Proteins (immunology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Nucleotidyltransferases (immunology)
• Real-Time Polymerase Chain Reaction
• Signal Transduction (immunology)