title: Influenza virus targets the mRNA export machinery and the nuclear pore complex.
abstract: The NS1 protein of influenza A virus is a major virulence factor that is essential for pathogenesis. NS1 functions to impair innate and adaptive immunity by inhibiting host signal transduction and gene expression, but its mechanisms of action remain to be fully elucidated. We show here that NS1 forms an inhibitory complex with NXF1/TAP, p15/NXT, Rae1/mrnp41, and E1B-AP5, which are key constituents of the mRNA export machinery that interact with both mRNAs and nucleoporins to direct mRNAs through the nuclear pore complex. Increased levels of NXF1, p15, or Rae1 revert the mRNA export blockage induced by NS1. Furthermore, influenza virus down-regulates Nup98, a nucleoporin that is a docking site for mRNA export factors. Reduced expression of these mRNA export factors renders cells highly permissive to influenza virus replication, demonstrating that proper levels of key constituents of the mRNA export machinery protect against influenza virus replication. Because Nup98 and Rae1 are induced by interferons, down-regulation of this pathway is likely a viral strategy to promote viral replication. These findings demonstrate previously undescribed influenza-mediated viral-host interactions and provide insights into potential molecular therapies that may interfere with influenza infection.
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9039, USA.
authors.forename: Neal
authors.initials: N
authors.lastname: Satterly
authors.forename: Pei-Ling
authors.initials: PL
authors.lastname: Tsai
authors.forename: Jan
authors.initials: J
authors.lastname: van Deursen
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Nussenzveig
authors.forename: Yaming
authors.initials: Y
authors.lastname: Wang
authors.forename: Paula A
authors.initials: PA
authors.lastname: Faria
authors.forename: Agata
authors.initials: A
authors.lastname: Levay
authors.forename: David E
authors.initials: DE
authors.lastname: Levy
authors.forename: Beatriz M A
authors.initials: BM
authors.lastname: Fontoura
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D015536:Down-Regulation / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D009980:Influenza A virus / Q000472:pathogenicity / Q000502:physiology*; D051379:Mice; D008969:Molecular Sequence Data; D022022:Nuclear Pore / Q000378:metabolism* / Q000821:virology*; D028861:Nuclear Pore Complex Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D017361:Viral Nonstructural Proteins / Q000502:physiology; D014774:Virulence
chemical_list: C085820:INS1 protein, influenza virus; D028861:Nuclear Pore Complex Proteins; C465451:Nup98 protein, human; D012333:RNA, Messenger; D017361:Viral Nonstructural Proteins