Journal Article

RIG-I triggers a signaling-abortive anti-SARS-CoV-2 defense in human lung cells

Sato, Seiichi, Sotoyama, Yuki, Orba, Yasuko, Yamauchi, Hajime, Takaoka, Akinori, Sawa, Hirofumi, Yamada, Taisho, Sasaki, Michihito

2021

Overview

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. RIG-I is a cytosolic nucleic acid sensor triggering type I IFN production. Takaoka and colleagues find that RIG-I recognizes SARS-CoV-2 RNA in a noncanonical manner and fails to activate type I IFN, but it directly restricts viral replication.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 3' Untranslated regions / 631/250/254 / 631/250/255/2514 / 631/250/262/2106/2518 / 631/326/596/4130 / A549 Cells / Acids / Adenosine triphosphatase / Animals / Antiviral drugs / Biomedical and Life Sciences / Biomedicine / Cell Line / Cell Line, Tumor / Cellular signal transduction / Chlorocebus aethiops / Chronic obstructive pulmonary disease / Coronaviruses / COVID-19 / COVID-19 - immunology / DEAD Box Protein 58 - immunology / Development and progression / DNA helicase / DNA-directed RNA polymerase / Dogs / Genetic aspects / Genomes / Health aspects / HEK293 Cells / Humans / Immune response / Immunological research / Immunology / Infectious Diseases / Interferon / Interferon Lambda / Interferon Type I - immunology / Interferons - immunology / Letter / Lung - immunology / Lung - virology / Lung diseases / Madin Darby Canine Kidney Cells / Mitochondria / Nucleic acids / Obstructive lung disease / Pandemics / Pattern recognition receptors / Proteins / Pulmonary Disease, Chronic Obstructive - immunology / Receptors, Immunologic - immunology / Replication / Retinoic acid / RNA helicase / RNA polymerase / RNA-Dependent RNA Polymerase - immunology / RNA-directed RNA polymerase / SARS-CoV-2 - immunology / Severe acute respiratory syndrome coronavirus 2 / Sf9 Cells / Signal Transduction - immunology / Spike protein / Vero Cells / Viral infections / Viral Proteins - immunology