TREX1 Deficiency Triggers Cell-Autonomous Immunity in a cGAS-Dependent Manner
TREX1 Deficiency Triggers Cell-Autonomous Immunity in a cGAS-Dependent Manner
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DOI：
10.4049/jimmunol.1400737
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发表时间：
2014-06-15
影响因子：
4.4
通讯作者：
Hornung, Veit
中科院分区：
文献类型：
--
作者：
Ablasser, Andrea;Hemmerling, Inga;Hornung, Veit
DNA的胞质检测对于启动抗病毒免疫是至关重要的，但也可以在内源性核酸被感测的情况下引起自身免疫。人类3 '修复核酸外切酶1（TREX 1）的突变与I型IFN相关的自身免疫性疾病Aicardi-Goutie' res综合征有关。在不存在TREX 1的情况下驱动不减弱的I型IFN应答的确切机制仅部分被理解，但似乎可能是内源性DNA物质的积累通过激活胞质DNA受体触发细胞自主免疫应答。在这篇文章中，我们证明，敲除DNA传感器环GMP-AMP合酶完全废除自发诱导的干扰素刺激基因TREX 1缺陷细胞。这些发现表明环GMP-AMP合酶的启动自身DNA诱导的自身免疫性疾病的关键作用，从而提供了新的治疗方法的重要意义。
Cytosolic detection of DNA is crucial for the initiation of antiviral immunity but can also cause autoimmunity in the context of endogenous nucleic acids being sensed. Mutations in the human 3 ' repair exonuclease 1 (TREX1) have been linked to the type I IFN-associated autoimmune disease Aicardi-Goutie` res syndrome. The exact mechanisms driving unabated type I IFN responses in the absence of TREX1 are only partly understood, but it appears likely that accumulation of endogenous DNA species triggers a cell-autonomous immune response by activating a cytosolic DNA receptor. In this article, we demonstrate that knocking out the DNA sensor cyclic GMP-AMP synthase completely abrogates spontaneous induction of IFN-stimulated genes in TREX1-deficient cells. These findings indicate a key role of cyclic GMP-AMP synthase for the initiation of self-DNA-induced autoimmune disorders, thus providing important implications for novel therapeutic approaches.