Mankan Arun K, Schmidt Tobias, Chauhan Dhruv, Goldeck Marion, Höning Klara, Gaidt Moritz, Kubarenko Andrew V, Andreeva Liudmila, Hopfner Karl-Peter, Hornung Veit
Institute of Molecular Medicine, University Hospital University of Bonn, Bonn, Germany.
Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital University of Bonn, Bonn, Germany.
EMBO J. 2014 Dec 17;33(24):2937-46. doi: 10.15252/embj.201488726. Epub 2014 Nov 25.
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.
细胞内对非自身以及自身核酸的识别可引发强效促炎和抗病毒细胞因子反应。最近，已证明环鸟苷酸合成酶（cGAS）对于识别细胞质双链DNA至关重要。双链DNA与cGAS结合会导致合成2'-5'-环状二核苷酸（cGAMP），然后cGAMP与内质网驻留蛋白干扰素基因刺激蛋白（STING）结合。这会启动一个信号级联反应，触发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双链RNA或双链DNA上，但细胞质中的RNA:DNA杂交体是否也能被先天免疫系统感知仍未得到探索。通过研究合成的RNA:DNA杂交体，我们确实观察到在这类分子进行细胞质递送后会产生强烈的I型干扰素反应。在人单核细胞白血病细胞系（THP-1）基因敲除细胞中的研究表明，对RNA:DNA杂交体的识别完全归因于cGAS-STING途径。此外，体外研究表明，重组cGAS在识别RNA:DNA杂交体时会产生cGAMP。总之，我们的研究结果将RNA:DNA杂交体引入为一类新型的细胞内病原体相关分子模式（PAMP）分子，并描述了双链DNA之外的另一种cGAS配体。
