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Nat Commun. 2015 Jan 20;6:5853. doi: 10.1038/ncomms6853.

DNase II-dependent DNA digestion is required for DNA sensing by TLR9.

Author information

1
Division of Innate Immunity, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minatoku, Tokyo 108-8639, Japan.
2
Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan.
3
Faculty of Life Sciences, Department of Molecular Biosciences, Kyoto Sangyo University, Kyoto 603-8555, Japan.
4
1] Division of Innate Immunity, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minatoku, Tokyo 108-8639, Japan [2] CREST, JST, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan.
5
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
6
1] CREST, JST, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan [2] Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
7
Department of Cell Biology and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida 33136, USA.
8
1] Division of Innate Immunity, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minatoku, Tokyo 108-8639, Japan [2] Laboratory of Innate Immunity, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minatoku, Tokyo 108-8639, Japan.

Abstract

DNase II digests DNA in endolysosomes. In the absence of DNase II, undigested DNA activates cytoplasmic DNA-sensing pathways. Little is known, however, about the role of DNase II in endolysosomal DNA sensing by TLR9. Here we show that DNase II is required for TLR9. We test two types of TLR9 ligands, CpG-A and CpG-B, and show that only CpG-A response is impaired in DNase II-deficient dendritic cells (DCs). Enzymatically inactive DNase II mutants cannot rescue CpG-A responses. DNase II cleaves CpG-A from 20-mer to 11-12-mer. The 3'11-mer CpG-A fragment activates DNase II-deficient DCs. CpG-A shows higher co-localization with LAMP-2(+) lysosomes than CpG-B and induces DNase II localization in LAMP-2(+) lysosomes. Moreover, we demonstrate that DNase II is required for TLR9 activation by bacterial genomic DNA. Taken together, these results demonstrate that TLR9 responds to DNA fragments generated by DNase II.

PMID:
25600358
DOI:
10.1038/ncomms6853
[Indexed for MEDLINE]

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