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Review
. 2009 Jun;11(6):863-71.
doi: 10.1111/j.1462-5822.2009.01309.x. Epub 2009 Mar 12.

A new player in a deadly game: influenza viruses and the PI3K/Akt signalling pathway

Christina Ehrhardt  1 , Stephan Ludwig
Affiliations
Review

A new player in a deadly game: influenza viruses and the PI3K/Akt signalling pathway

Christina Ehrhardt et al. Cell Microbiol. 2009 Jun.

Abstract

Upon influenza A virus infection of cells, a wide variety of antiviral and virus-supportive signalling pathways are induced. Phosphatidylinositol-3-kinase (PI3K) is a recent addition to the growing list of signalling mediators that are activated by these viruses. Several studies have addressed the role of PI3K and the downstream effector protein kinase Akt in influenza A virus-infected cells. PI3K/Akt signalling is activated by diverse mechanisms in a biphasic manner and is required for multiple functions during infection. While the kinase supports activation of the interferon regulatory factor-3 during antiviral interferon induction, it also exhibits virus supportive functions. In fact, PI3K not only regulates a very early step during viral entry but also results in suppression of premature apoptosis at later stages of infection. The latter function is dependent on the expression of the viral non-structural protein-1 (A/NS1). It has been shown that PI3K activation occurs by direct interaction of A/NS1 with the p85 regulatory subunit and interaction sites of A/NS1 and p85 have now been mapped in detail. Here, we summarize the current knowledge on influenza virus-induced PI3K signalling and how this pathway supports viral propagation.

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Figures

Figure 1
Figure 1
Schematic presentation of PI3K‐dependent signalling pathways. For details see the text. Abbreviations not mentioned in the text: TSC1/2, TSC 1 and 2 genes; RHEB, Ras‐homologue enriched in brain); EIFEBP1, eukaryotic initiation factor 4E binding protein 1.
Figure 2
Figure 2
PI3K activation and function in the influenza virus‐infected cell. For details see the text.
Figure 3
Figure 3
Schematic illustration of the binding domain structure of A/NS1 and p85β.
A. Influenza A virus NS1 encompasses up to 237 aa, depending on the strain. The RNA binding domain is located within the first 73 aa and three putative binding motifs (bm) for SH domains have been identified (SH2‐bm, SH3‐bm‐1, SH3‐bm‐2) (presumed motifs for A/NS1 interaction with p85β or Crk/CrkL are depicted). The asterisk indicates the binding sequence responsible for interaction with the inter‐SH2 domain (iSH2) domain of p85β.
B. The regulatory subunit p85β encompasses 724 aa and harbours one N‐terminal SH3 domain, two SH2 domains flanking the iSH2, one BH (Bcr/Rac GAP homology) domain and two proline‐rich motifs (triangle) (Vanhaesebroeck et al., 2005). Interaction of the N‐terminal SH3 domain of p85β with A/NS1 was shown to be stronger than with the C‐terminal SH2 domain. Recently, the iSH2 domain has been identified as additional interaction site for A/NS1, whereby the Valine 573 seems to be the most important aa responsible for interaction.
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