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RIG-I triggers a signaling-abortive anti-SARS-CoV-2 defense in human lung cells.
Nat Immunol. 2021 07; 22(7):820-828.NI

Abstract

Efficient immune responses against viral infection are determined by sufficient activation of nucleic acid sensor-mediated innate immunity1,2. 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.

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Authors+Show Affiliations

Yamada T
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.
Sato S
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.
Sotoyama Y
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.
Orba Y
Division of Molecular Pathobiology, Research Center for Zoonosis Control, Hokkaido University, Sapporo, Japan. International Collaboration Unit, Research Center for Zoonosis Control, Hokkaido University, Sapporo, Japan.
Sawa H
Division of Molecular Pathobiology, Research Center for Zoonosis Control, Hokkaido University, Sapporo, Japan. International Collaboration Unit, Research Center for Zoonosis Control, Hokkaido University, Sapporo, Japan. Global Virus Network, Baltimore, MD, USA.
Yamauchi H
Division of Signaling in Cancer and Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
Sasaki M
Division of Molecular Pathobiology, Research Center for Zoonosis Control, Hokkaido University, Sapporo, Japan.
Takaoka A
Division of Signaling in Cancer and Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan. takaoka@igm.hokudai.ac.jp. Molecular Medical Biochemistry Unit, Biological Chemistry and Engineering Course, Graduate School of Chemical Sciences and Engineering, Hokkaido University, Sapporo, Japan. takaoka@igm.hokudai.ac.jp.

MeSH

A549 CellsAnimalsCOVID-19Cell LineCell Line, TumorChlorocebus aethiopsDEAD Box Protein 58DogsHEK293 CellsHumansInterferon Type IInterferonsLungMadin Darby Canine Kidney CellsPulmonary Disease, Chronic ObstructiveRNA-Dependent RNA PolymeraseReceptors, ImmunologicSARS-CoV-2Sf9 CellsSignal TransductionVero CellsViral ProteinsInterferon Lambda

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

33976430

Citation

Yamada, Taisho, et al. "RIG-I Triggers a Signaling-abortive anti-SARS-CoV-2 Defense in Human Lung Cells." Nature Immunology, vol. 22, no. 7, 2021, pp. 820-828.
Yamada T, Sato S, Sotoyama Y, et al. RIG-I triggers a signaling-abortive anti-SARS-CoV-2 defense in human lung cells. Nat Immunol. 2021;22(7):820-828.
Yamada, T., Sato, S., Sotoyama, Y., Orba, Y., Sawa, H., Yamauchi, H., Sasaki, M., & Takaoka, A. (2021). RIG-I triggers a signaling-abortive anti-SARS-CoV-2 defense in human lung cells. Nature Immunology, 22(7), 820-828. https://doi.org/10.1038/s41590-021-00942-0
Yamada T, et al. RIG-I Triggers a Signaling-abortive anti-SARS-CoV-2 Defense in Human Lung Cells. Nat Immunol. 2021;22(7):820-828. PubMed PMID: 33976430.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - RIG-I triggers a signaling-abortive anti-SARS-CoV-2 defense in human lung cells. AU - Yamada,Taisho, AU - Sato,Seiichi, AU - Sotoyama,Yuki, AU - Orba,Yasuko, AU - Sawa,Hirofumi, AU - Yamauchi,Hajime, AU - Sasaki,Michihito, AU - Takaoka,Akinori, Y1 - 2021/05/11/ PY - 2020/12/15/received PY - 2021/04/26/accepted PY - 2021/5/13/pubmed PY - 2021/7/2/medline PY - 2021/5/12/entrez SP - 820 EP - 828 JF - Nature immunology JO - Nat Immunol VL - 22 IS - 7 N2 - Efficient immune responses against viral infection are determined by sufficient activation of nucleic acid sensor-mediated innate immunity1,2. 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. SN - 1529-2916 UR - https://www.unboundmedicine.com/medline/citation/33976430/RIG_I_triggers_a_signaling_abortive_anti_SARS_CoV_2_defense_in_human_lung_cells_ DB - PRIME DP - Unbound Medicine ER -