Cellular DDX21 RNA Helicase Inhibits Influenza A Virus Replication but Is Counteracted by the Viral NS1 Protein

• Published in: Cell host & microbe 2014-04, Vol.15 (4), p.484-493
• Main Authors: Chen, Guifang, Liu, Chien-Hung, Zhou, Ligang, Krug, Robert M.
• Format: Article
• Language: English
• Subjects: Animals; Binding Sites; Cell Line, Tumor; DEAD-box RNA Helicases - genetics; DEAD-box RNA Helicases - metabolism; Dogs; HEK293 Cells; HeLa Cells; Humans; Influenza A virus - genetics; Madin Darby Canine Kidney Cells; Nucleic Acid Synthesis Inhibitors; Protein Binding; Protein Biosynthesis - genetics; Protein Structure, Tertiary; RNA Interference; RNA, Small Interfering; RNA, Viral - biosynthesis; Viral Nonstructural Proteins - metabolism; Viral Proteins - metabolism; Virus Replication
• ISSN: 1931-3128; 1934-6069
• DOI: 10.1016/j.chom.2014.03.002

Influenza A virus RNA synthesis is catalyzed by the viral polymerase comprised of the PA, PB1, and PB2 proteins. We show that the host DDX21 RNA helicase restricts influenza A virus by binding PB1 and inhibiting polymerase assembly, resulting in reduced viral RNA and protein synthesis. Later during infection, the viral NS1 protein overcomes this restriction by binding to DDX21 and displacing PB1. DDX21 binds to a region of the NS1 N-terminal domain that also participates in other critical functions. A virus mutant whose NS1 protein is unable to bind DDX21 exhibits reduced viral protein synthesis at both late and early times of infection, a phenotype converted to wild-type upon DDX21 knockdown. As sequential interaction of PB1 and NS1 with DDX21 leads to temporal regulation of viral gene expression, influenza A virus likely uses the DDX21-NS1 interaction not only to overcome restriction, but also to regulate the viral life cycle. [Display omitted] •DDX21 inhibits influenza viral RNA synthesis by binding the PB1 polymerase subunit•Viral NS1 protein binds DDX21 and displaces PB1 to restore viral RNA synthesis•DDX21 binds to a region of NS1 that also participates in other crucial functions•A virus mutant whose NS1 does not bind DDX21 exhibits depressed late-gene expression Influenza viral RNA synthesis is catalyzed by the viral polymerase containing PA, PB1, and PB2 proteins. Chen et al. show that DDX21 RNA helicase inhibits influenza virus RNA synthesis by binding PB1 and preventing polymerase assembly. The viral NS1 protein overcomes this restriction by interacting with DDX21 and releasing PB1.