title: Positive feedback regulation of type I IFN production by the IFN-inducible DNA sensor cGAS.
abstract: Rapid and robust induction of type I IFN (IFN-I) is a critical event in host antiviral innate immune response. It has been well demonstrated that cyclic GMP-AMP (cGAMP) synthase (cGAS) plays an important role in sensing cytosolic DNA and triggering STING dependent signaling to induce IFN-I. However, it is largely unknown how cGAS itself is regulated during pathogen infection and IFN-I production. In this study, we show that pattern recognition receptor (PRR) ligands, including lipid A, LPS, poly(I:C), poly(dA:dT), and cGAMP, induce cGAS expression in an IFN-I-dependent manner in both mouse and human macrophages. Further experiments indicated that cGAS is an IFN-stimulated gene (ISG), and two adjacent IFN-sensitive response elements (ISREs) in the promoter region of cGAS mediate the induction of cGAS by IFN-I. Additionally, we show that optimal production of IFN-β triggered by poly (dA:dT) or HSV-1 requires IFNAR signaling. Knockdown of the constitutively expressed DNA sensor DDX41 attenuates poly(dA:dT)-triggered IFN-β production and cGAS induction. By analyzing the dynamic expression of poly(dA:dT)-induced IFN-β and cGAS transcripts, we have found that induction of IFN-β is earlier than cGAS. Furthermore, we have provided evidence that induction of cGAS by IFN-I meditates the subsequent positive feedback regulation of DNA-triggered IFN-I production. Thus, our study not only provides a novel mechanism of modulating cGAS expression, but also adds another layer of regulation in DNA-triggered IFN-I production by induction of cGAS.
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095;
authors.forename: Feng
authors.initials: F
authors.lastname: Ma
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095; and.
authors.forename: Bing
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095;
authors.forename: Su-yang
authors.initials: SY
authors.lastname: Liu
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095;
authors.forename: Shankar S
authors.initials: SS
authors.lastname: Iyer
authors.affiliation: Division of Oral Biology and Medicine, School of Dentistry and Broad Stem Cell Research Center, University of California, Los Angeles, Los Angeles, CA 90095.
authors.forename: Yongxin
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095;
authors.forename: Aiping
authors.initials: A
authors.lastname: Wu
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095; gcheng@mednet.ucla.edu.
authors.forename: Genhong
authors.initials: G
authors.lastname: Cheng
mesh_terms: D000818:Animals; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D004797:Enzyme-Linked Immunosorbent Assay; D025461:Feedback, Physiological; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D015151:Immunoblotting; D007370:Interferon Type I / Q000096:biosynthesis* / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009713:Nucleotidyltransferases / Q000276:immunology* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
chemical_list: D007370:Interferon Type I; D009713:Nucleotidyltransferases; C578391:cGAS protein, mouse; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase