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

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DNA-Mediated Cyclic GMP−AMP Synthase− Dependent and −Independent Regulation of Innate Immune Responses DNA-Mediated Cyclic GMP−AMP Synthase− Dependent and −Independent Regulation of Innate Immune Responses This information is current as Kou Motani, Shinji Ito and Shigekazu Nagata of September 28, 2021. J Immunol 2015; 194:4914-4923; Prepublished online 8 April 2015; doi: 10.4049/jimmunol.1402705 http://www.jimmunol.org/content/194/10/4914 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2015/04/08/jimmunol.140270 Material 5.DCSupplemental References This article cites 57 articles, 19 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/194/10/4914.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 28, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2015 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology DNA-Mediated Cyclic GMP–AMP Synthase–Dependent and –Independent Regulation of Innate Immune Responses Kou Motani,*,† Shinji Ito,‡ and Shigekazu Nagata* Cytoplasmic DNA activates cyclic GMP–AMP synthase (cGAS) to produce cyclic 29-5939-59GMP–AMP dinucleotide (295 9cGAMP). The binding of 2959cGAMP 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 2959cGAMP-dependent STING activation induced highly upregulated CXCL10 gene expression. Formation of a distinct STING dimer, which was detected by native PAGE, was induced by 2959cGAMP, but not 39-5939-59cGAMP. Analysis of DNase II2/2 mice, which constitutively produce IFN-b and CXCL10, showed the accumulation of 2959cGAMP in their fetal livers and spleens, suggesting that the undigested DNA accumulating in DNase II2/2 cells may have leaked from the lysosomes into the cytoplasm. 2/2 9 9 The DNase II mouse embryonic fibroblasts produced 2 5 cGAMP in a cGAS-dependent manner during apoptotic cell engulf- Downloaded from ment. However, cGAS deficiency did not impair the STING-dependent upregulation of CXCL10 in DNase II2/2 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. The Journal of Immu- nology, 2015, 194: 4914–4923. he innate immune system in vertebrates is activated by their DNA is degraded by the lysosomal DNase, DNase II. We http://www.jimmunol.org/ pathogens via the recognition of pathogen-associated mo- previously reported that the impaired degradation of apoptotic or T lecular patterns (1). The genomic DNAs of various patho- pyrenocyte DNA in DNase II2/2 macrophages causes a strong gens function as pathogen-associated molecular patterns (2, 3) that inflammatory response that leads to lethal anemia or polyarthritis are recognized by DNA sensors in endosomes/lysosomes or the (7–10). Similarly, the impaired degradation of endogenous cyto- cytoplasm. Recognition by the DNA sensors activates the expression plasmic retrotransposon DNA by a mutant form of three prime of various cytokines, such as IFN-b, CXCL10, and TNF-a,which repair exonuclease (also known as DNase III), causes Aicardi- leads to the induction of acquired immunity. Normally, endogenous Goutieres syndrome, a systemic lupus erythematosus type of au- self-DNA is localized to the nucleus or mitochondria and does not toimmune disease (11). elicit an immune response. However, mislocalized DNA can activate DNA-induced signaling that leads to innate immune activation by guest on September 28, 2021 innate immunity, leading to sterile inflammation accompanied by has been extensively studied (2–4, 12). TLR9 recognizes viral and autoimmunity (4). bacterial nonmethylated CpG DNA in endosomes and transduces Many cells undergo apoptosis during animal development and signals through the Myd88 adaptor protein to activate two tran- tissue turnover and are engulfed by macrophages (5). During de- scription factors: IFN response regulatory factor (IRF)7, which finitive erythropoiesis, pyrenocytes, nuclei surrounded by plasma induces the upregulation of IFN-b and CXCL10, and NF-kB, which membrane, are released from erythroblasts at erythroblastic is- upregulates inflammatory cytokines (13). The accumulation of en- lands and engulfed by macrophages (6). After their engulfment, dogenous self-DNA in the lysosomes of DNase II2/2 cells or in the apoptotic cells and pyrenocytes are taken up by lysosomes, and cytoplasm of three prime repair exonuclease 12/2 cells leads to IFN-b and CXCL10 gene upregulation via IRF3 or IRF7, but this process is TLR9-independent (14, 15), suggesting the presence of *Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, additional DNA sensor(s). † Sakyo-ku, Kyoto 606-8501, Japan; Division of Cell Signaling, Fujii Memorial In- Stimulator of IFN genes (STING), originally identified as an stitute of Medical Sciences, University of Tokushima, Tokushima 770-8503, Japan; and ‡Medical Research Support Center, Graduate School of Medicine, Kyoto Uni- adaptor protein located in the endoplasmic reticulum that activates versity, Sakyo-ku, Kyoto 606-8501, Japan IFN genes (16), was recently shown to bind cyclic dinucleotides Received for publication October 28, 2014. Accepted for publication March 11, such as cyclic di-GMP (c-di-GMP) and cyclic di-AMP produced 2015. in bacteria (17, 18). Subsequently, a series of reports showed that This work was supported in part by Grants-in-Aid for Specially Promoted Research mammalian cells produce a similar, but distinct, cyclic dinucleo- from the Japan Society for the Promotion of Science (to S.N.), and by a Grant-in-Aid for Research Activity Start-up from the Japan Society for the Promotion of Science tide (or cyclic GMP–AMP [cGAMP]) in response to cytoplasmic (to K.M.). DNA (3). The binding of DNA to cGAMP synthase (cGAS) Address correspondence and reprint requests to Prof. Shigekazu Nagata, Department activates the enzyme to synthesize 29-59,39-59-cGAMP (2959- of Medical Chemistry, Graduate School of Medicine, Kyoto University, Yoshida- cGAMP) from ATP and GTP (19–22). The 2959-cGAMP then Konoe, Sakyo-ku, Kyoto 606-8501, Japan. E-mail address: [email protected]. kyoto-u.ac.jp binds to STING and induces its dimerization, which leads to The online version of this article contains supplemental material. TBK1 activation and IRF3 phosphorylation, and then to the in- b Abbreviations used in this article: c-di-GMP, cyclic di-GMP; cGAMP, cyclic GMP–AMP; duction of IFN- gene expression (23). The innate immune re- cGAS, cGAMP synthase; CRISPR, clustered regularly interspaced short palindromic sponse to DNA viruses as well as reverse-transcribed retroviral repeats; FasL, Fas ligand; IRF, IFN response regulatory factor; MEF, mouse embryonic DNA is dependent on STING (24, 25) as well as cGAS (26, 27). fibroblast; poly(I:C), polyinosinic-polycytidylic acid; STING, stimulator of IFN genes. Surprisingly, the activation of innate immunity by the undigested 2/2 Copyright Ó 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$25.00 DNA of apoptotic cells engulfed by DNase II cells is also www.jimmunol.org/cgi/doi/10.4049/jimmunol.1402705 The Journal of Immunology 4915 STING-dependent (28). However, the mechanism by which DNA CTGCGGCCCGCAAAGGT-39 and 59-TAAAACCTTTGCGGGCCGCA- is recognized in DNase II2/2 cells has not yet been elucidated. GCTTTCCGCGTGGGCC-39, and 59-CACCGAAAGCTGCGGCCCGC- 9 9 9 In this study, we found that DNase II2/2 mouse embryonic AAAG-3 and 5 -AAACCTTTGCGGGCCGCAGCTTTC-3 ) were de- 9 9 signed using the CRISPR Design Tool at Dr. Zhang’s Laboratory (http:// fibroblasts (MEFs) produced 2 5 -cGAMP in a cGAS-dependent www.genome-engineering.org/crispr/?page_id=41). They were inserted manner, upon apoptotic cell engulfment. However, the apoptotic into BbsI-digested pX260 or pX330 (Addgene, Cambridge, MA) and used 2 2 cell engulfment-mediated induction of CXCL10 expression in these to transfect DNase II / MEFs by electroporation using the NEPA21 cells was independent of cGAS. DNA introduced into DNase II2/2 system (135 V, 10 ms; Nepagene, Chiba, Japan). After 3-d incubation at 37˚C, the cells were subjected to limiting dilution, and the clones con- MEFs by lipofection also activated CXCL10 gene expression in taining mutated STING or cGAS gene were identified by sequencing the a cGAS-independent manner. These results suggest the presence of PCR products flanking the CRSPR-target site. Primers for PCR were as additional DNA sensor(s) that recognizes lysosome-localized DNA follows: STING, 59-CTCAGTGCTGAGACTCAGAC-39 and 59-AGAG- and activates the STING-mediated innate immunity. GTCCTACGTTCAATTC-39; cGAS, 59-ATACTGACCGGCTACGTTCC- 39 and 59-CAACTTTATTCACCGTCTCG-39. Materials and Methods Introduction of DNA, RNA, and cGAMP into MEFs Mice, cells, and reagents To introduce DNA or dsRNA into MEFs, plasmid DNA or poly(I:C) was C57BL/6J mice were purchased from Japan SLC. CAD2/2 and DNase II2/2 incubated for 20 min with Lipofectamine 2000 at a ratio of 1:2 (w/v) in IFNIR2/2 mice were described previously (8, 9). Mice were housed in DMEM, and added to cells at a final concentration of 0.1–1 mg/ml. In some 5 a specific pathogen-free facility at the Kyoto University, Graduate School cases, MEFs (3 3 10 in 0.1 ml Opti-MEM containing 1.0 mgDNAor of Medicine, and all animal experiments were carried out in accordance RNA) were subjected to electroporation at 125 V for 2.5 ms using the NEPA21 system.
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