{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T08:36:32Z","timestamp":1792139792413,"version":"4.4.0"},"reference-count":39,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2021,3,2]],"date-time":"2021-03-02T00:00:00Z","timestamp":1614643200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF-2019R1A2C1005961"],"award-info":[{"award-number":["NRF-2019R1A2C1005961"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the coronavirus disease 2019 (COVID-19) that has resulted in the current pandemic. The lack of highly efficacious antiviral drugs that can manage this ongoing global emergency gives urgency to establishing a comprehensive understanding of the molecular pathogenesis of SARS-CoV-2. We characterized the role of the nucleocapsid protein (N) of SARS-CoV-2 in modulating antiviral immunity. Overexpression of SARS-CoV-2 N resulted in the attenuation of retinoic acid inducible gene-I (RIG-I)-like receptor-mediated interferon (IFN) production and IFN-induced gene expression. Similar to the SARS-CoV-1 N protein, SARS-CoV-2 N suppressed the interaction between tripartate motif protein 25 (TRIM25) and RIG-I. Furthermore, SARS-CoV-2 N inhibited polyinosinic: polycytidylic acid [poly(I:C)]-mediated IFN signaling at the level of Tank-binding kinase 1 (TBK1) and interfered with the association between TBK1 and interferon regulatory factor 3 (IRF3), subsequently preventing the nuclear translocation of IRF3. We further found that both type I and III IFN production induced by either the influenza virus lacking the nonstructural protein 1 or the Zika virus were suppressed by the SARS-CoV-2 N protein. Our findings provide insights into the molecular function of the SARS-CoV-2 N protein with respect to counteracting the host antiviral immune response.<\/jats:p>","DOI":"10.3390\/cells10030530","type":"journal-article","created":{"date-parts":[[2021,3,2]],"date-time":"2021-03-02T10:36:37Z","timestamp":1614681397000},"page":"530","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":123,"title":["SARS-CoV-2 Nucleocapsid Protein Targets RIG-I-Like Receptor Pathways to Inhibit the Induction of Interferon Response"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5423-0440","authenticated-orcid":false,"given":"Soo Jin","family":"Oh","sequence":"first","affiliation":[{"name":"BK21 Graduate Program, Department of Biomedical Sciences, College of Medicine, Korea University Guro Hospital, Seoul\r\n\t  08308, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ok Sarah","family":"Shin","sequence":"additional","affiliation":[{"name":"BK21 Graduate Program, Department of Biomedical Sciences, College of Medicine, Korea University Guro Hospital, Seoul\r\n\t  08308, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/S0140-6736(20)30183-5","article-title":"Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China","volume":"395","author":"Huang","year":"2020","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1016\/j.immuni.2020.05.002","article-title":"Immunology of COVID-19: Current State of the Science","volume":"52","author":"Vabret","year":"2020","journal-title":"Immunity"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1038\/s41579-018-0118-9","article-title":"Origin and evolution of pathogenic coronaviruses","volume":"17","author":"Cui","year":"2019","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1056\/NEJMoa2001017","article-title":"A Novel Coronavirus from Patients with Pneumonia in China, 2019","volume":"382","author":"Zhu","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1146\/annurev-immunol-032713-120231","article-title":"Interferon-stimulated genes: A complex web of host defenses","volume":"32","author":"Schneider","year":"2014","journal-title":"Annu. Rev. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1146\/annurev-micro-020518-115759","article-title":"Human Coronavirus: Host-Pathogen Interaction","volume":"73","author":"Fung","year":"2019","journal-title":"Annu. Rev. Microbiol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Sa Ribero, M., Jouvenet, N., Dreux, M., and Nisole, S. (2020). Interplay between SARS-CoV-2 and the type I interferon response. PLoS Pathog., 16.","DOI":"10.1371\/journal.ppat.1008737"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1400","DOI":"10.1093\/cid\/ciaa410","article-title":"Comparative replication and immune activation profiles of SARS-CoV-2 and SARS-CoV in human lungs: An ex vivo study with implications for the pathogenesis of COVID-19","volume":"71","author":"Chu","year":"2020","journal-title":"Clin. Infect. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1093\/infdis\/jiaa356","article-title":"Attenuated Interferon and Proinflammatory Response in SARS-CoV-2-Infected Human Dendritic Cells Is Associated With Viral Antagonism of STAT1 Phosphorylation","volume":"222","author":"Yang","year":"2020","journal-title":"J. Infect. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1016\/j.cell.2020.04.026","article-title":"Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19","volume":"181","author":"Liu","year":"2020","journal-title":"Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1126\/science.abc6027","article-title":"Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients","volume":"369","author":"Hadjadj","year":"2020","journal-title":"Science"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1006\/viro.1998.9508","article-title":"Influenza A virus lacking the NS1 gene replicates in interferon-deficient systems","volume":"252","author":"Egorov","year":"1998","journal-title":"Virology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"286","DOI":"10.4110\/in.2016.16.5.286","article-title":"Enhanced Viral Replication by Cellular Replicative Senescence","volume":"16","author":"Kim","year":"2016","journal-title":"Immune Netw."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1007\/s12275-016-6383-2","article-title":"MDA7\/IL-24 is an anti-viral factor that inhibits influenza virus replication","volume":"54","author":"Seong","year":"2016","journal-title":"J. Microbiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/j.jid.2018.07.038","article-title":"Insights into ZIKV-Mediated Innate Immune Responses in Human Dermal Fibroblasts and Epidermal Keratinocytes","volume":"139","author":"Kim","year":"2019","journal-title":"J. Investig. Dermatol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Kim, J.A., Seong, R.K., Kumar, M., and Shin, O.S. (2018). Favipiravir and Ribavirin Inhibit Replication of Asian and African Strains of Zika Virus in Different Cell Models. Viruses, 10.","DOI":"10.3390\/v10020072"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2061","DOI":"10.1080\/22221751.2020.1821581","article-title":"mRNA and miRNA profiling of Zika virus-infected human umbilical cord mesenchymal stem cells identifies miR-142-5p as an antiviral factor","volume":"9","author":"Seong","year":"2020","journal-title":"Emerg. Microbes Infect."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Oh, S.J., Lim, S., Song, M.J., Ahn, J.H., Lee, C.H., and Shin, O.S. (2019). Whole Transcriptome Analyses Reveal Differential mRNA and microRNA Expression Profiles in Primary Human Dermal Fibroblasts Infected with Clinical or Vaccine Strains of Varicella Zoster Virus. Pathogens, 8.","DOI":"10.3390\/pathogens8040183"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1080\/22221751.2020.1719902","article-title":"Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan","volume":"9","author":"Chan","year":"2020","journal-title":"Emerg. Microbes Infect."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1016\/j.jmb.2007.02.069","article-title":"Structure of the SARS coronavirus nucleocapsid protein RNA-binding dimerization domain suggests a mechanism for helical packaging of viral RNA","volume":"368","author":"Chen","year":"2007","journal-title":"J. Mol. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.virusres.2007.03.015","article-title":"SARS coronavirus and innate immunity","volume":"133","author":"Frieman","year":"2008","journal-title":"Virus Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1038\/s41421-020-00208-3","article-title":"SARS-CoV-2 N protein antagonizes type I interferon signaling by suppressing phosphorylation and nuclear translocation of STAT1 and STAT2","volume":"6","author":"Mu","year":"2020","journal-title":"Cell Discov."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Hu, Y., Li, W., Gao, T., Cui, Y., Jin, Y., Li, P., Ma, Q., Liu, X., and Cao, C. (2017). The Severe Acute Respiratory Syndrome Coronavirus Nucleocapsid Inhibits Type I Interferon Production by Interfering with TRIM25-Mediated RIG-I Ubiquitination. J. Virol., 91.","DOI":"10.1128\/JVI.02143-16"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1016\/j.imbio.2017.07.002","article-title":"Schlafen 14 (SLFN14) is a novel antiviral factor involved in the control of viral replication","volume":"222","author":"Seong","year":"2017","journal-title":"Immunobiology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1418","DOI":"10.1080\/22221751.2020.1780953","article-title":"SARS-CoV-2 nsp13, nsp14, nsp15 and orf6 function as potent interferon antagonists","volume":"9","author":"Yuen","year":"2020","journal-title":"Emerg. Microbes Infect."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2991","DOI":"10.3390\/v6082991","article-title":"The coronavirus nucleocapsid is a multifunctional protein","volume":"6","author":"McBride","year":"2014","journal-title":"Viruses"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Cong, Y., Ulasli, M., Schepers, H., Mauthe, M., V\u2019Kovski, P., Kriegenburg, F., Thiel, V., de Haan, C.A.M., and Reggiori, F. (2020). Nucleocapsid Protein Recruitment to Replication-Transcription Complexes Plays a Crucial Role in Coronaviral Life Cycle. J. Virol., 94.","DOI":"10.1128\/JVI.01925-19"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1644","DOI":"10.1016\/j.vaccine.2008.01.025","article-title":"Priming with rAAV encoding RBD of SARS-CoV S protein and boosting with RBD-specific peptides for T cell epitopes elevated humoral and cellular immune responses against SARS-CoV infection","volume":"26","author":"Du","year":"2008","journal-title":"Vaccine"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"10669","DOI":"10.1074\/jbc.M509233200","article-title":"The nucleocapsid protein of severe acute respiratory syndrome-coronavirus inhibits the activity of cyclin-cyclin-dependent kinase complex and blocks S phase progression in mammalian cells","volume":"281","author":"Surjit","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"13848","DOI":"10.1128\/JVI.79.22.13848-13855.2005","article-title":"Assembly of severe acute respiratory syndrome coronavirus RNA packaging signal into virus-like particles is nucleocapsid dependent","volume":"79","author":"Hsieh","year":"2005","journal-title":"J. Virol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1128\/JVI.01782-06","article-title":"Severe acute respiratory syndrome coronavirus open reading frame (ORF) 3b, ORF 6, and nucleocapsid proteins function as interferon antagonists","volume":"81","author":"Frieman","year":"2007","journal-title":"J. Virol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Reghunathan, R., Jayapal, M., Hsu, L.Y., Chng, H.H., Tai, D., Leung, B.P., and Melendez, A.J. (2005). Expression profile of immune response genes in patients with Severe Acute Respiratory Syndrome. BMC Immunol., 6.","DOI":"10.1186\/1471-2172-6-2"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"6604","DOI":"10.1128\/JVI.00009-13","article-title":"Tropism of and innate immune responses to the novel human betacoronavirus lineage C virus in human ex vivo respiratory organ cultures","volume":"87","author":"Chan","year":"2013","journal-title":"J. Virol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1007\/s11262-010-0544-x","article-title":"SARS-CoV nucleocapsid protein antagonizes IFN-beta response by targeting initial step of IFN-beta induction pathway, and its C-terminal region is critical for the antagonism","volume":"42","author":"Lu","year":"2011","journal-title":"Virus Genes"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Chang, C.Y., Liu, H.M., Chang, M.F., and Chang, S.C. (2020). Middle East Respiratory Syndrome Coronavirus Nucleocapsid Protein Suppresses Type I and Type III Interferon Induction by Targeting RIG-I Signaling. J. Virol., 94.","DOI":"10.1128\/JVI.00099-20"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1016\/j.immuni.2011.05.003","article-title":"Immune signaling by RIG-I-like receptors","volume":"34","author":"Loo","year":"2011","journal-title":"Immunity"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1038\/nri1900","article-title":"IRFs: Master regulators of signalling by Toll-like receptors and cytosolic pattern-recognition receptors","volume":"6","author":"Honda","year":"2006","journal-title":"Nat. Rev. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1016\/j.immuni.2006.08.009","article-title":"Type I interferon [corrected] gene induction by the interferon regulatory factor family of transcription factors","volume":"25","author":"Honda","year":"2006","journal-title":"Immunity"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1111\/j.1365-2443.2010.01427.x","article-title":"Ser386 phosphorylation of transcription factor IRF-3 induces dimerization and association with CBP\/p300 without overall conformational change","volume":"15","author":"Takahasi","year":"2010","journal-title":"Genes Cells"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/3\/530\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:31:33Z","timestamp":1760160693000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/3\/530"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,2]]},"references-count":39,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2021,3]]}},"alternative-id":["cells10030530"],"URL":"https:\/\/doi.org\/10.3390\/cells10030530","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,2]]}}}