DDX5/METTL3-METTL14/YTHDF2 Axis Regulates Replication of Influenza A Virus

• Published in: Microbiology spectrum 2022-06, Vol.10 (3), p.e0109822
• Main Authors: Zhao, Lingcai, Zhao, Yongzhen, Liu, Qingzheng, Huang, Jingjin, Lu, Yuanlu, Ping, Jihui
• Format: Article
• Language: English
• Subjects: antiviral immunity; DDX5; DEAD-box RNA Helicases - genetics; DEAD-box RNA Helicases - metabolism; Host-Microbial Interactions; Humans; IFN-β; Immunity, Innate; Influenza A virus - genetics; influenza viruses; Influenza, Human - genetics; Interferon-beta - genetics; Interleukin-6; Methyltransferases; METTL3-METTL14/YTHDF2; Orthomyxoviridae Infections; Research Article; RNA; RNA, Messenger; RNA-Binding Proteins; Transcription Factors
• ISSN: 2165-0497; 2165-0497
• DOI: 10.1128/spectrum.01098-22

DEAD-box helicase 5 (DDX5), a member of the DEAD/H-box helicases, is known to participate in all aspects of RNA metabolism. However, its regulatory effect in antiviral innate immunity during replication of influenza virus remains unclear. Herein, we found that human DDX5 promotes replication of influenza virus in A549 cells. Moreover, our results further revealed that DDX5 relies on its N terminus to interact with the nucleoprotein (NP) of influenza virus, which is independent of RNA. Of course, we also observed colocalization of DDX5 with NP in the context of transfection or infection. However, influenza virus infection had no significant effect on the protein expression and nucleocytoplasmic distribution of DDX5. Importantly, we found that DDX5 suppresses antiviral innate immunity induced by influenza virus infection. Mechanistically, DDX5 downregulated the mRNA levels of interferon beta (IFN-β), interleukin 6 (IL-6), and DHX58 via the METTL3-METTL14/YTHDF2 axis. We revealed that DDX5 bound antiviral transcripts and regulated immune responses through YTHDF2-dependent mRNA decay. Taken together, our data demonstrate that the DDX5/METTL3-METTL14/YTHDF2 axis regulates the replication of influenza A virus. The replication and transcription of influenza virus depends on the participation of many host factors in cells. Exploring the relationship between viruses and host factors will help us fully understand the characteristics and pathogenic mechanisms of influenza viruses. In this study, we showed that DDX5 interacted with the NP of influenza virus. We demonstrated that DDX5 downregulated the expression of IFN-β and IL-6 and the transcription of antiviral genes downstream from IFN-β in influenza virus-infected A549 cells. Additionally, DDX5 downregulated the mRNA levels of antiviral transcripts via the METTL3-METTL14/YTHDF2 axis. Our findings provide a novel perspective to understand the mechanism by which DDX5 regulates antiviral immunity.