RIG-I triggers a signaling-abortive anti-SARS-CoV-2 defense in human lung cells
RIG-I triggers a signaling-abortive anti-SARS-CoV-2 defense in human lung cells
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DOI：
10.1038/s41590-021-00942-0
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发表时间：
2021-05-11
影响因子：
30.5
通讯作者：
Takaoka, Akinori
中科院分区：
文献类型：
--
作者：
Yamada, Taisho;Sato, Seiichi;Takaoka, Akinori
针对病毒感染的有效免疫应答由核酸传感器介导的先天免疫的充分激活决定（1，2）。由严重急性呼吸道综合征冠状病毒2（SARS-CoV-2）引起的2019年冠状病毒病仍然是一种持续的全球大流行病。因此，阐明其先天识别机制是控制该病毒的一个迫切挑战。在这里，我们表明，视黄酸诱导基因-I（RIG-I）充分抑制SARS冠状病毒-2复制在人肺细胞中的I/III型干扰素（IFN）的独立方式。RIG-I通过解旋酶结构域识别SARS-CoV-2 RNA基因组的3 '非翻译区，但不识别C-末端结构域。这种新的RIG-I识别模式不刺激其ATP酶，从而中止常规线粒体抗病毒信号传导蛋白依赖性途径的激活，这与缺乏细胞因子诱导一致。然而，RIG-I与病毒基因组的相互作用直接消除了病毒RNA依赖性RNA聚合酶对复制第一步的介导。一致地，RIG-I的基因消融允许肺细胞产生表达病毒刺突蛋白的病毒颗粒。相反，抗SARS-CoV-2活性通过全反式维甲酸治疗通过上调来自慢性阻塞性肺疾病患者的原代肺细胞中RIG-I蛋白表达而恢复。因此，我们的研究结果表明，RIG-I作为一个抑制因子在早期阶段的SARS冠状病毒-2感染人肺细胞的独特作用。
Efficient immune responses against viral infection are determined by sufficient activation of nucleic acid sensor-mediated innate immunity(1,2). Coronavirus disease 2019, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains an ongoing global pandemic. It is an urgent challenge to clarify the innate recognition mechanism to control this virus. Here we show that retinoic acid-inducible gene-I (RIG-I) sufficiently restrains SARS-CoV-2 replication in human lung cells in a type I/III interferon (IFN)-independent manner. RIG-I recognizes the 3 ' untranslated region of the SARS-CoV-2 RNA genome via the helicase domains, but not the C-terminal domain. This new mode of RIG-I recognition does not stimulate its ATPase, thereby aborting the activation of the conventional mitochondrial antiviral-signaling protein-dependent pathways, which is in accordance with lack of cytokine induction. Nevertheless, the interaction of RIG-I with the viral genome directly abrogates viral RNA-dependent RNA polymerase mediation of the first step of replication. Consistently, genetic ablation of RIG-I allows lung cells to produce viral particles that expressed the viral spike protein. By contrast, the anti-SARS-CoV-2 activity was restored by all-trans retinoic acid treatment through upregulation of RIG-I protein expression in primary lung cells derived from patients with chronic obstructive pulmonary disease. Thus, our findings demonstrate the distinctive role of RIG-I as a restraining factor in the early phase of SARS-CoV-2 infection in human lung cells.