Influenza virus targets the mRNA export machinery and the nuclear pore complex (PNAS, 2007, 104:1853-1858)

報告日期: 2008/10/07
報告時間: 15:10/16:00
報告學生: 郭懿瑩
講評老師: 王貞仁

Influenza virus targets the mRNA export machinery and the
nuclear pore complex
Neal Satterly , Pei-Ling Tsai, Jan van Deursen , Daniel R. Nussenzveig , Yaming Wang , Paula A. Faria , Agata Levay , David E. Levy , and Beatriz M. A. Fontoura.
PNAS 104 (6) 1853-1858 Feb, 2007

Speaker: Yih-Ying Kuo
Commentator: Dr. Jen-Ren Wang
Time: 15:10-16:00, Oct. 7, 2008
Place: Room 602, College of medicine

  The non-structural protein 1 of influenza A virus (NS1) is a multifunctional protein essential for viral virulence and induced pathogenesis. It can interact with dsRNA and a series of host proteins to operate several post-transcriptional and translational controls on mRNAs and the suppression of IFN-mediated antiviral responses. NS1 contains both nuclear localization and exporting signals (NLS & NES); however, the later is only active in the presence of influenza virus RNPs (vRNPs). In the cytoplasm, NS1 can form a complex with RIG-I and interfere with PKR and the RNase L pathway to antagonize the innate immune response. In the nuclear, NS1 can inhibit cellular mRNA processing by interacting with polyadenylation and splicing factors (CPSF, PABII, and NS1-BP), leading to the blockage of the 3’ ends cellular pre-mRNA posttranscriptional processing and subsequent mRNA nuclear export. As TAP (NXF1)/p15 (NXT) is the receptor involved in the major cellular mRNA export pathway for mRNP complex and can interact with Nup98 or other nucleoporins to form the mRNP transport machinery with the nuclear/cytoplasm shuttling factor Rae1/mrnp41/Gle2, the authors investigate whether NS1 interacts with the mRNA nuclear export machinery and nuclear pore complex (nucleoporins or Nups) to explore the possible mechanism of NS1 induced inhibition of mRNA export,. Their results indicate that NS1 forms an inhibitory complex by direct interacting with NXF1, Rae1, p15 and E1B-AP5, which are key components of the mRNA transport machinery. These interactions are independent of RNA recognition and increased expression of NXF1, Rae1, or p15 reverts the mRNA export blockage induced by NS1. In addition, influenza virus infection down-regulates Nup98, and low levels of Rae1 and Nup98 induce higher susceptibility to virus induced cell death. Since Nup98 and Rae1 are constituents of mRNA export pathway that are targeted by viruses and regulated by IFN, down- regulation of the pathway therefore is likely a viral strategy to promote viral replication. This study provides significant insights of NS1 in modulating the mRNP exporting machinery and highlights the importance of the mRNP machinery to be used as a therapeutic target.

1. PNAS Feb.6, 2007; 104 (6): 1853–1858 Influenza virus targets the mRNA export machinery and the nuclear pore complex.
2. PNAS May.2, 2006 ;103 (18): 7100–7105 The primary function of RNA binding by the influenza A virus NS1 protein in infected cells: Inhibiting the 2’-5’ oligo (A) synthetase RNase L pathway.
3. TRENDS in Cell Biology Jun. 2003; 13 (6) 319:327 The interplay of nuclear mRNP assembly, mRNA surveillance and export.