Division of Signaling in Cancer and Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
Molecular Medical Biochemistry Unit, Biological Chemistry and Engineering Course, Graduate School of Chemical Sciences and Engineering, Hokkaido University, Sapporo, Japan.
Nat Immunol. 2021 Jul;22(7):820-828. doi: 10.1038/s41590-021-00942-0. Epub 2021 May 11.
Efficient immune responses against viral infection are determined by sufficient activation of nucleic acid sensor-mediated innate immunity. 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.
有效的抗病毒感染免疫反应取决于核酸传感器介导的固有免疫的充分激活。由严重急性呼吸系统综合征冠状病毒 2（SARS-CoV-2）引起的 2019 年冠状病毒病（COVID-19）仍然是一场持续的全球大流行。阐明固有识别机制以控制这种病毒是一个紧迫的挑战。在这里，我们表明，视黄酸诱导基因-I（RIG-I）以一种不依赖 I/III 型干扰素（IFN）的方式，在人肺细胞中充分抑制 SARS-CoV-2 的复制。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 端结构域。这种新的 RIG-I 识别模式不会刺激其 ATP 酶活性，从而阻止了传统的线粒体抗病毒信号蛋白依赖性途径的激活，这与细胞因子诱导的缺失是一致的。然而，RIG-I 与病毒基因组的相互作用直接阻断了病毒 RNA 依赖性 RNA 聚合酶介导的复制的第一步。一致地，RIG-I 的基因缺失允许肺细胞产生表达病毒刺突蛋白的病毒颗粒。相比之下，全反式视黄酸通过上调源自慢性阻塞性肺疾病患者的原代肺细胞中的 RIG-I 蛋白表达，恢复了抗 SARS-CoV-2 活性。因此，我们的研究结果表明，RIG-I 在 SARS-CoV-2 感染人肺细胞的早期阶段作为一种限制因子发挥着独特的作用。
