https://scholars.lib.ntu.edu.tw/handle/123456789/493398
標題: | Middle East respiratory syndrome coronavirus nucleocapsid protein suppresses type I and type III interferon induction by targeting RIG-I signaling | 作者: | Chang, Chi-You HELENE MINYI LIU MING-FU CHANG SHIN CHANG |
公開日期: | 15-四月-2020 | 來源出版物: | Journal of virology | 摘要: | Type I and type III interferons (IFNs) are the frontlines of antiviral defense mechanism that trigger hundreds of downstream antiviral genes. In this study, we observed that MERS-CoV nucleocapsid (N) protein suppresses type I and 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-, 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 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 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. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/493398 | ISSN: | 0022-538X 1098-5514 |
DOI: | 10.1128/JVI.00099-20 |
顯示於: | 生物化學暨分子生物學科研究所 |
在 IR 系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。