ADAR1 RNA editing regulates endothelial cell functions via the MDA-5 RNA sensing signaling pathway.
ADAR1 RNA editing regulates endothelial cell functions via the MDA-5 RNA sensing signaling pathway.
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DOI：
10.26508/lsa.202101191
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发表时间：
2022-03
影响因子：
4.4
通讯作者：
Wang Q
中科院分区：
文献类型：
--
作者：
Guo X;Liu S;Yan R;Nguyen V;Zenati M;Billiar TR;Wang Q
内皮细胞中的细胞 RNA 转录本，尤其是 SINE RNA，需要通过 A-to-I RNA 编辑酶 ADAR1 进行广泛的编辑，ADAR1 通过调节 MDA-5 介导的 RNA 传感信号通路对新生儿的生存至关重要。 RNA 传感信号通路作为先天免疫的重要抗病毒机制已得到充分研究。然而，其在未感染细胞中的作用尚未得到彻底表征。在这里，我们证明了 RNA 传感信号通路也与内皮细胞 (EC) 中的内源性细胞 RNA 发生反应，并且该反应受到 RNA 编辑酶 ADAR1 的调节。细胞 RNA 测序分析表明，EC RNA 能够承受广泛的 RNA 编辑，特别是在短散布核元件的 RNA 转录本中。 EC 特异性删除 ADAR1 显着降低了短散布核元件 RNA 的编辑水平，导致多器官明显损伤的小鼠新生死亡。全基因组基因表达分析揭示了显着的先天免疫激活，干扰素刺激基因的表达显着升高。然而，通过删除细胞 RNA 受体 MDA-5 来阻断 RNA 传感信号通路可以阻止干扰素刺激的基因表达，从而使新生小鼠免于死亡。这一证据表明，RNA 编辑/RNA 传感信号通路可显着调节 EC 功能，代表了一种调节 EC 功能的新分子机制。
Cellular RNA transcripts in endothelial cells, especially the SINE RNAs, need extensive editing by the A-to-I RNA editing enzyme ADAR1, which is essential for neonatal survival by regulating the MDA-5–mediated RNA-sensing signaling pathway. The RNA-sensing signaling pathway has been well studied as an essential antiviral mechanism of innate immunity. However, its role in non-infected cells is yet to be thoroughly characterized. Here, we demonstrated that the RNA sensing signaling pathway also reacts to the endogenous cellular RNAs in endothelial cells (ECs), and this reaction is regulated by the RNA-editing enzyme ADAR1. Cellular RNA sequencing analysis showed that EC RNAs endure extensive RNA editing, especially in the RNA transcripts of short interspersed nuclear elements. The EC-specific deletion of ADAR1 dramatically reduced the editing level on short interspersed nuclear element RNAs, resulting in newborn death in mice with damage evident in multiple organs. Genome-wide gene expression analysis revealed a prominent innate immune activation with a dramatically elevated expression of interferon-stimulated genes. However, blocking the RNA sensing signaling pathway by deletion of the cellular RNA receptor MDA-5 prevented interferon-stimulated gene expression and rescued the newborn mice from death. This evidence demonstrated that the RNA-editing/RNA-sensing signaling pathway dramatically modulates EC function, representing a novel molecular mechanism for the regulation of EC functions.