Short single-stranded DNA degradation products augment the activation of Toll-like receptor 9.
Short single-stranded DNA degradation products augment the activation of Toll-like receptor 9.
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DOI：
10.1038/ncomms15363
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发表时间：
2017-05-22
影响因子：
16.6
通讯作者：
Benčina M
中科院分区：
文献类型：
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作者：
Pohar J;Lainšček D;Ivičak-Kocjan K;Cajnko MM;Jerala R;Benčina M
Toll样受体在内小体中会遇到多种降解产物。TLR7和TLR8已被证明可被RNA降解产物激活。在这里，我们表明，虽然TLR9需要超过20个核苷酸的单链DNA才能产生强大的反应，但TLR9的激活可被短至2个核苷酸的含CpG的寡核苷酸(SODN)增强，而sODN本身不会在细胞培养中诱导激活，也不会在小鼠中诱导激活。SODN还结合含有单个CpG基序的ODN激活人TLR9，该基序本身不激活人TLR9。SODN的特异序列基序以及ODN和sODN的共定位表明，激活机制涉及到ODN和sODN与TLR9的结合。SODN通过哺乳动物基因组DNA增强TLR9的激活，表明短DNA降解产物在内体对感染或自身免疫性疾病的反应中的作用，特别是在限制ODN浓度的情况下。DNA降解产物经常出现在内体中，但它们如何调节Toll样受体的激活尚不清楚。在这里，作者们表明，短于两个核苷酸的单链DNA可以增强较长的DNA寡核苷酸激活Toll样受体的能力。
Toll-like receptors encounter a diversity of degradation products in endosomes. TLR7 and TLR8 have been shown to be activated by RNA degradation products. Here we show that although TLR9 requires single-stranded DNA longer than 20 nucleotides for a robust response, TLR9 activation is augmented by CpG-containing oligodeoxyribonucleotides (sODNs) as short as 2 nucleotides, which, by themselves, do not induce activation in cell cultures, as well as in mice. sODNs also activate human TLR9 in combination with ODNs containing a single CpG motif that by themselves do not activate human TLR9. The specific sequence motif of sODN and colocalization of ODN and sODN suggest that the mechanism of activation involves binding of both ODN and sODN to TLR9. sODNs augment TLR9 activation by mammalian genomic DNA indicating the role of short DNA degradation products in the endosomes in response to infection or in autoimmune disease, particularly at limiting concentrations of ODNs. DNA degradation products are frequently found in the endosome, but how they regulate the activation of Toll-like receptors is not known. Here the authors show that single-stranded DNA as short as two nucleotides can enhance the ability of longer DNA oligonucleotides to activate Toll-like receptors.