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Middle East Respiratory Syndrome Coronavirus Nucleocapsid Protein Suppresses Type I and Type III Interferon Induction by Targeting RIG-I Signaling.
J Virol. 2020 Jun 16; 94(13)JV

Abstract

Type I and type III interferons (IFNs) are the frontline of antiviral defense mechanisms that trigger hundreds of downstream antiviral genes. In this study, we observed that MERS-CoV nucleocapsid (N) protein suppresses type I and type III IFN gene expression. The N protein suppresses Sendai virus-induced IFN-β and IFN-λ1 by reducing their promoter activity and mRNA levels, as well as downstream IFN-stimulated genes (ISGs). Retinoic acid-inducible gene I (RIG-I) is known to recognize viral RNA and induce IFN expression through tripartite motif-containing protein 25 (TRIM25)-mediated ubiquitination of RIG-I caspase activation and recruitment domains (CARDs). We discovered that MERS-CoV N protein suppresses RIG-I-CARD-induced, but not MDA5-CARD-induced, IFN-β and IFN-λ1 promoter activity. By interacting with TRIM25, N protein impedes RIG-I ubiquitination and activation and inhibits the phosphorylation of transcription factors IFN-regulatory factor 3 (IRF3) and NF-κB that are known to be important for IFN gene activation. By employing a recombinant Sindbis virus-EGFP replication system, we showed that viral N protein downregulated the production of not only IFN mRNA but also bioactive IFN proteins. Taken together, MERS-CoV N protein functions as an IFN antagonist. It suppresses RIG-I-induced type I and type III IFN production by interfering with TRIM25-mediated RIG-I ubiquitination. Our study sheds light on the pathogenic mechanism of how MERS-CoV causes disease.IMPORTANCE MERS-CoV causes death of about 35% of patients. Published studies showed that some coronaviruses are capable of suppressing interferon (IFN) expression in the early phase of infection and MERS-CoV proteins can modulate host immune response. In this study, we demonstrated that MERS-CoV nucleocapsid (N) protein suppresses the production of both type I and type III IFNs via sequestering TRIM25, an E3 ubiquitin ligase that is essential for activating the RIG-I signaling pathway. Ectopic expression of TRIM25 rescues the suppressive effect of the N protein. In addition, the C-terminal domain of the viral N protein plays a pivotal role in the suppression of IFN-β promoter activity. Our findings reveal how MERS-CoV evades innate immunity and provide insights into the interplay between host immune response and viral pathogenicity.

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Authors+Show Affiliations

Chang CY
Institute of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan.
Liu HM
Institute of Biochemistry and Molecular Biology, National Taiwan University College of Medicine, Taipei, Taiwan.
Chang MF
Institute of Biochemistry and Molecular Biology, National Taiwan University College of Medicine, Taipei, Taiwan mfchang@ntu.edu.tw scchang093@ntu.edu.tw.
Chang SC
Institute of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan mfchang@ntu.edu.tw scchang093@ntu.edu.tw.

MeSH

CARD Signaling Adaptor ProteinsCell LineCoronavirus InfectionsDEAD Box Protein 58Gene Expression RegulationHost-Pathogen InteractionsHumansInterferon Regulatory Factor-3Interferon Type IInterferonsMiddle East Respiratory Syndrome CoronavirusNucleocapsid ProteinsPromoter Regions, GeneticProtein BindingReceptors, ImmunologicSignal TransductionTranscription FactorsTripartite Motif ProteinsUbiquitin-Protein LigasesInterferon Lambda

Pub Type(s)

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

Language

eng

PubMed ID

32295922

Citation

Chang, Chi-You, et al. "Middle East Respiratory Syndrome Coronavirus Nucleocapsid Protein Suppresses Type I and Type III Interferon Induction By Targeting RIG-I Signaling." Journal of Virology, vol. 94, no. 13, 2020.
Chang CY, Liu HM, Chang MF, et al. Middle East Respiratory Syndrome Coronavirus Nucleocapsid Protein Suppresses Type I and Type III Interferon Induction by Targeting RIG-I Signaling. J Virol. 2020;94(13).
Chang, C. Y., Liu, H. M., Chang, M. F., & Chang, S. C. (2020). Middle East Respiratory Syndrome Coronavirus Nucleocapsid Protein Suppresses Type I and Type III Interferon Induction by Targeting RIG-I Signaling. Journal of Virology, 94(13). https://doi.org/10.1128/JVI.00099-20
Chang CY, et al. Middle East Respiratory Syndrome Coronavirus Nucleocapsid Protein Suppresses Type I and Type III Interferon Induction By Targeting RIG-I Signaling. J Virol. 2020 Jun 16;94(13) PubMed PMID: 32295922.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Middle East Respiratory Syndrome Coronavirus Nucleocapsid Protein Suppresses Type I and Type III Interferon Induction by Targeting RIG-I Signaling. AU - Chang,Chi-You, AU - Liu,Helene Minyi, AU - Chang,Ming-Fu, AU - Chang,Shin C, Y1 - 2020/06/16/ PY - 2020/1/17/received PY - 2020/4/9/accepted PY - 2020/4/17/pubmed PY - 2020/9/12/medline PY - 2020/4/17/entrez KW - MERS-CoV KW - RIG-I KW - TRIM25 KW - interferon-β KW - interferon-λ1 KW - nucleocapsid protein JF - Journal of virology JO - J Virol VL - 94 IS - 13 N2 - Type I and type III interferons (IFNs) are the frontline of antiviral defense mechanisms that trigger hundreds of downstream antiviral genes. In this study, we observed that MERS-CoV nucleocapsid (N) protein suppresses type I and type III IFN gene expression. The N protein suppresses Sendai virus-induced IFN-β and IFN-λ1 by reducing their promoter activity and mRNA levels, as well as downstream IFN-stimulated genes (ISGs). Retinoic acid-inducible gene I (RIG-I) is known to recognize viral RNA and induce IFN expression through tripartite motif-containing protein 25 (TRIM25)-mediated ubiquitination of RIG-I caspase activation and recruitment domains (CARDs). We discovered that MERS-CoV N protein suppresses RIG-I-CARD-induced, but not MDA5-CARD-induced, IFN-β and IFN-λ1 promoter activity. By interacting with TRIM25, N protein impedes RIG-I ubiquitination and activation and inhibits the phosphorylation of transcription factors IFN-regulatory factor 3 (IRF3) and NF-κB that are known to be important for IFN gene activation. By employing a recombinant Sindbis virus-EGFP replication system, we showed that viral N protein downregulated the production of not only IFN mRNA but also bioactive IFN proteins. Taken together, MERS-CoV N protein functions as an IFN antagonist. It suppresses RIG-I-induced type I and type III IFN production by interfering with TRIM25-mediated RIG-I ubiquitination. Our study sheds light on the pathogenic mechanism of how MERS-CoV causes disease.IMPORTANCE MERS-CoV causes death of about 35% of patients. Published studies showed that some coronaviruses are capable of suppressing interferon (IFN) expression in the early phase of infection and MERS-CoV proteins can modulate host immune response. In this study, we demonstrated that MERS-CoV nucleocapsid (N) protein suppresses the production of both type I and type III IFNs via sequestering TRIM25, an E3 ubiquitin ligase that is essential for activating the RIG-I signaling pathway. Ectopic expression of TRIM25 rescues the suppressive effect of the N protein. In addition, the C-terminal domain of the viral N protein plays a pivotal role in the suppression of IFN-β promoter activity. Our findings reveal how MERS-CoV evades innate immunity and provide insights into the interplay between host immune response and viral pathogenicity. SN - 1098-5514 UR - https://www.unboundmedicine.com/medline/citation/32295922/Middle_East_Respiratory_Syndrome_Coronavirus_Nucleocapsid_Protein_Suppresses_Type_I_and_Type_III_Interferon_Induction_by_Targeting_RIG_I_Signaling_ DB - PRIME DP - Unbound Medicine ER -