Suppressive oligodeoxynucleotides containing TTAGGG motifs inhibit cGAS activation in human monocytes.
Suppressive oligodeoxynucleotides containing TTAGGG motifs inhibit cGAS activation in human monocytes.
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DOI：
10.1002/eji.201747338
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发表时间：
2018-04
影响因子：
5.4
通讯作者：
Bode C
中科院分区：
文献类型：
--
作者：
Steinhagen F;Zillinger T;Peukert K;Fox M;Thudium M;Barchet W;Putensen C;Klinman D;Latz E;Bode C
I型干扰素（IFN）是自身免疫性疾病如系统性红斑狼疮（SLE）和Aicardi-Goutières综合征（AGS）的关键介质。最近发现的环-GMP-AMP（cGAMP）合酶（cGAS）诱导响应于胞质DNA的I型IFN的产生，并且可能与SLE和AGS相关。哺乳动物端粒中含有重复TTAGGG基序的抑制性寡脱氧核苷酸（ODN）已被证明可用于治疗包括SLE在内的自身免疫性疾病。在这项研究中，我们证明了抑制性ODN A151有效地抑制了响应于胞质DNA的cGAS的活化，从而抑制了人单核细胞的I型IFN产生。此外，使用TREX 1缺陷型单核细胞，A151消除了响应于DNA内源性积累的cGAS活化。我们证明A151以与DNA竞争的方式阻止cGAS活化。A151的这种抑制活性依赖于端粒序列和硫代磷酸酯骨架。据我们所知，这份报告提出了第一个能够阻断自身DNA的cGAS抑制剂。总的来说，这些发现可能会导致开发针对cGAS激活引起的IFN驱动的病理学的新疗法。
Type I interferon (IFN) is a critical mediator of autoimmune diseases such as systemic lupus erythematosus (SLE) and Aicardi–Goutières Syndrome (AGS). The recently discovered cyclic-GMP-AMP (cGAMP) synthase (cGAS) induces the production of type I IFN in response to cytosolic DNA and is potentially linked to SLE and AGS. Suppressive oligodeoxynucleotides (ODN) containing repetitive TTAGGG motifs present in mammalian telomeres have proven useful in the treatment of autoimmune diseases including SLE. In this study, we demonstrate that the suppressive ODN A151 effectively inhibits activation of cGAS in response to cytosolic DNA, thereby inhibiting type I IFN production by human monocytes. In addition, A151 abrogated cGAS activation in response to endogenous accumulation of DNA using TREX1-deficient monocytes. We demonstrate that A151 prevents cGAS activation in a manner that is competitive with DNA. This suppressive activity of A151 was dependent on both telomeric sequence and phosphorothioate backbone. To our knowledge this report presents the first cGAS inhibitor capable of blocking self-DNA. Collectively, these findings might lead to the development of new therapeutics against IFN-driven pathologies due to cGAS activation.
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影响因子：
9.3
作者：
Bayik D;Gursel I;Klinman DM
通讯作者：
Klinman DM
影响因子：
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作者：
Gursel, I;Gursel, M;Klinman, DM
通讯作者：
Klinman, DM
影响因子：
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Otsu, Kinya
影响因子：
8.8
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Schaefer, Simon T.;Franken, Lars;Limmer, Andreas
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Limmer, Andreas
影响因子：
64.8
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West, A. Phillip;Khoury-Hanold, William;Staron, Matthew;Tal, Michal C.;Pineda, Cristiana M.;Lang, Sabine M.;Bestwick, Megan;Duguay, Brett A.;Raimundo, Nuno;MacDuff, Donna A.;Kaech, Susan M.;Smiley, James R.;Means, Robert E.;Iwasaki, Akiko;Shadel, Gerald S.
通讯作者：
Shadel, Gerald S.