Nonsegmented Negative-Sense RNA Viruses Utilize N(6)-Methyladenosine (m(6)A) as a Common Strategy To Evade Host Innate Immunity
| Autor: | Qinzhe Liu, Jiangbo Wei, Sadeem Ahmad, Mark E. Peeples, Amit Sharma, Jianrong Li, Elizabeth L. Kairis, Chuan He, Youling Gao, Dominique Garcin, Sun Hur, Mijia Lu, Miaoge Xue, Yuexiu Zhang, Hai-Tao Wang, Zijie Zhang |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Gene Expression Regulation
Viral Adenosine viruses Immunology Microbiology 03 medical and health sciences chemistry.chemical_compound Gene Knockout Techniques 0302 clinical medicine RNA Virus Infections Interferon Virology Gene expression medicine Humans RNA Processing Post-Transcriptional 030304 developmental biology Genetics 0303 health sciences Innate immune system biology Host Microbial Interactions RNA Methyltransferases Rhabdoviridae biology.organism_classification Immunity Innate Pneumoviridae chemistry Type I interferon signaling pathway A549 Cells Insect Science Interferon Type I Negative-Sense RNA Viruses Pathogenesis and Immunity RNA Viral N6-Methyladenosine 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | J Virol |
| Popis: | N(6)-Methyladenosine (m(6)A) is the most abundant internal RNA modification catalyzed by host RNA methyltransferases. As obligate intracellular parasites, many viruses acquire m(6)A methylation in their RNAs. However, the biological functions of viral m(6)A methylation are poorly understood. Here, we found that viral m(6)A methylation serves as a molecular marker for host innate immunity to discriminate self from nonself RNA and that this novel biological function of viral m(6)A methylation is universally conserved in several families in nonsegmented negative-sense (NNS) RNA viruses. Using m(6)A methyltransferase (METTL3) knockout cells, we produced m(6)A-deficient virion RNAs from the representative members of the families Pneumoviridae, Paramyxoviridae, and Rhabdoviridae and found that these m(6)A-deficient viral RNAs triggered significantly higher levels of type I interferon compared to the m(6)A-sufficient viral RNAs, in a RIG-I-dependent manner. Reconstitution of the RIG-I pathway revealed that m(6)A-deficient virion RNA induced higher expression of RIG-I, bound to RIG-I more efficiently, enhanced RIG-I ubiquitination, and facilitated RIG-I conformational rearrangement and oligomerization. Furthermore, the m(6)A binding protein YTHDF2 is essential for suppression of the type I interferon signaling pathway, including by virion RNA. Collectively, our results suggest that several families in NNS RNA viruses acquire m(6)A in viral RNA as a common strategy to evade host innate immunity. IMPORTANCE The nonsegmented negative-sense (NNS) RNA viruses share many common replication and gene expression strategies. There are no vaccines or antiviral drugs for many of these viruses. We found that representative members of the families Pneumoviridae, Paramyxoviridae, and Rhabdoviridae among the NNS RNA viruses acquire m(6)A methylation in their genome and antigenome as a means to escape recognition by host innate immunity via a RIG-I-dependent signaling pathway. Viral RNA lacking m(6)A methylation induces a significantly higher type I interferon response than m(6)A-sufficient viral RNA. In addition to uncovering m(6)A methylation as a common mechanism for many NNS RNA viruses to evade host innate immunity, this study discovered a novel strategy to enhance type I interferon responses, which may have important applications in vaccine development, as robust innate immunity will likely promote the subsequent adaptive immunity. |
| Databáze: | OpenAIRE |
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