Cytosolic RNA:DNA hybrids activate the cGAS-STING axis
Cytosolic RNA:DNA hybrids activate the cGAS-STING axis
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DOI：
10.15252/embj.201488726
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发表时间：
2014-12-17
期刊：
影响因子：
11.4
通讯作者：
Hornung, Veit
中科院分区：
文献类型：
--
作者：
Mankan, Arun K.;Schmidt, Tobias;Hornung, Veit
细胞内对非自体和自体核酸的识别可导致启动强效的促炎和抗病毒细胞因子反应。最近，cGAS被证明对细胞质dsDNA的识别至关重要。dsDNA与cGAS结合导致cGAMP（2'-5'）的合成，cGAMP随后与内质网驻留蛋白STING结合。这启动了一个信号级联，触发了抗病毒免疫反应的诱导。虽然大多数关于细胞内核酸的研究都集中在dsRNA或dsDNA上，但先天免疫系统是否也能感知胞质RNA:DNA杂交，这一问题尚未得到探讨。在研究合成RNA:DNA杂交体时，我们确实观察到这类分子在胞质内递送时有强烈的I型干扰素反应。对THP-1敲除细胞的研究表明，RNA:DNA杂交体的识别完全归因于cGAS-STING通路。此外，体外研究表明，重组cGAS通过RNA:DNA杂交识别产生cGAMP。总之，我们的研究结果介绍了RNA:DNA杂交体作为一类新的细胞内PAMP分子，并描述了dsDNA旁边的另一种cGAS配体。
Intracellular recognition of non-self and also self-nucleic acids can result in the initiation of potent pro-inflammatory and antiviral cytokine responses. Most recently, cGAS was shown to be critical for the recognition of cytoplasmic dsDNA. Binding of dsDNA to cGAS results in the synthesis of cGAMP(2'-5'), which then binds to the endoplasmic reticulum resident protein STING. This initiates a signaling cascade that triggers the induction of an antiviral immune response. While most studies on intracellular nucleic acids have focused on dsRNA or dsDNA, it has remained unexplored whether cytosolic RNA:DNA hybrids are also sensed by the innate immune system. Studying synthetic RNA:DNA hybrids, we indeed observed a strong type I interferon response upon cytosolic delivery of this class of molecule. Studies in THP-1 knockout cells revealed that the recognition of RNA:DNA hybrids is completely attributable to the cGAS-STING pathway. Moreover, in vitro studies showed that recombinant cGAS produced cGAMP upon RNA:DNA hybrid recognition. Altogether, our results introduce RNA:DNA hybrids as a novel class of intracellular PAMP molecules and describe an alternative cGAS ligand next to dsDNA.