Influenza A virus NS1 protein binds p85-b and activates phosphatidylinositol-3-kinase signaling

B. G. Hale, David Jackson, Y. H. Chen, R. A. Lamb, R. E. Randall

Research output: Contribution to journalArticlepeer-review

226 Citations (Scopus)

Abstract

Influenza A virus NS1 is a multifunctional protein, and in virus-infected cells NS1 modulates a number of host-cell processes by interacting with cellular factors. Here, we report that NS1 binds directly to p85 beta, a regulatory subunit of phosphatidylinositol-3-kinase (PI3K), but not to the related p85 alpha subunit. Activation of PI3K in influenza virus-infected cells depended on genome replication, and showed kinetics that correlated with NS1 expression. Additionally, it was found that expression of NS1 alone was sufficient to constitutively activate PI3K, causing the phosphorylation of a downstream mediator of PI3K signal transduction, Akt. Mutational analysis of a potential SH2-binding motif within NS1 indicated that the highly conserved tyrosine at residue 89 is important for both the interaction with p85 beta, and the activation of PI3K. A mutant influenza virus (A/Udorn/72) expressing NS1 with the Y89F amino acid substitution exhibited a small-plaque phenotype, and grew more slowly in tissue culture than WT virus. These data suggest that activation of PI3K signaling in influenza A virus-infected cells is important for efficient virus replication.

Original languageEnglish
Pages (from-to)14194-14199
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number38
DOIs
Publication statusPublished - 19 Sept 2006

Keywords

  • 1-Phosphatidylinositol 3-Kinase/ metabolism Amino Acid Substitution Animals Cell Line Enzyme Activation Humans Influenzavirus A/ metabolism Phosphorylation Protein Binding Proto-Oncogene Proteins c-akt/genetics/metabolism Recombinant Proteins/genetics/metabolism Signal Transduction/ physiology Tyrosine/metabolism Viral Nonstructural Proteins/genetics/ metabolism

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