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

被引：122

作者：

Chan, Mei Po ^{[1
]}

Onji, Masahiro ^{[2
]}

Fukui, Ryutaro ^{[1
]}

Kawane, Kohki ^{[3
]}

Shibata, Takuma ^{[1
,4
]}

Saitoh, Shin-ichiroh ^{[1
]}

Ohto, Umeharu ^{[5
]}

Shimizu, Toshiyuki ^{[4
,5
]}

Barber, Glen N. ^{[6
,7
]}

Miyake, Kensuke ^{[1
,8
]}

机构：

[1] Univ Tokyo, Inst Med Sci, Dept Microbiol & Immunol, Div Innate Immun,Minato Ku, Tokyo 1088639, Japan

[2] Okayama Univ, Grad Sch Med, Dept Gastroenterol & Hepatol, Kita Ku, Okayama 7008558, Japan

[3] Kyoto Sangyo Univ, Dept Mol Biosci, Fac Life Sci, Kyoto 6038555, Japan

[4] JST, CREST, Kawaguchi, Saitama 3320012, Japan

[5] Univ Tokyo, Grad Sch Pharmaceut Sci, Bunkyo Ku, Tokyo 1130033, Japan

[6] Univ Miami, Miller Sch Med, Dept Cell Biol, Miami, FL 33136 USA

[7] Univ Miami, Miller Sch Med, Sylvester Comprehens Canc Ctr, Miami, FL 33136 USA

[8] Univ Tokyo, Inst Med Sci, Ctr Expt Med & Syst Biol, Lab Innate Immun,Minato Ku, Tokyo 1088639, Japan

来源：

NATURE COMMUNICATIONS | 2015年 / 6卷

关键词：

DENDRITIC CELLS; ALPHA INDUCTION; MAMMALIAN DNA; RECEPTOR; 9; IDENTIFICATION; ADAPTER;

D O I：

10.1038/ncomms6853

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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 3011-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.

引用

页数：10

共 28 条

[1]

STING manifests self DNA-dependent inflammatory disease [J].