Cellular DDX21 RNA helicase inhibits influenza A virus replication but is counteracted by the viral NS1 protein.
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.
Department of Molecular Biosciences, Center of Infectious Disease, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX 78712, USA.
Guifang
G
Chen
Department of Molecular Biosciences, Center of Infectious Disease, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX 78712, USA.
Chien-Hung
CH
Liu
Department of Molecular Biosciences, Center of Infectious Disease, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX 78712, USA.
Ligang
L
Zhou
Department of Molecular Biosciences, Center of Infectious Disease, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX 78712, USA. Electronic address: rkrug@austin.utexas.edu.
Robert M
RM
Krug
D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D004285:Dogs; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D009980:Influenza A virus / Q000235:genetics*; D061985:Madin Darby Canine Kidney Cells; D019384:Nucleic Acid Synthesis Inhibitors; D011485:Protein Binding; D014176:Protein Biosynthesis / Q000235:genetics; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D034741:RNA, Small Interfering; D012367:RNA, Viral / Q000096:biosynthesis; D017361:Viral Nonstructural Proteins / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism*; D014779:Virus Replication
C085820:INS1 protein, influenza virus; D019384:Nucleic Acid Synthesis Inhibitors; D034741:RNA, Small Interfering; D012367:RNA, Viral; D017361:Viral Nonstructural Proteins; D014764:Viral Proteins; C077346:influenza virus polymerase basic protein 1; C501726:DDX21 protein, human; D053487:DEAD-box RNA Helicases