The nonstructural protein 1 (NS1) of influenza A virus performs a broad variety of
proviral activities in the infected cell, primarily mediating evasion from the host innate
immune response by being the main viral interferon antagonist. However, there are
several interactions whose biological relevance remains obscure, such as the ability of
NS1 to bind and activate class IA phosphoinositide 3-kinases
(PI3Ks). PI3Ks are highly
regulated lipid kinases that act as critical nodes in multiple cell signaling networks and
are also important proto-oncogenes.
This activation is mediated by NS1 binding specifically
to the p85β subunit. To better understand the consequences of this interaction, we
developed a bimolecular fluorescence complementation (BiFC) assay to selectively track
the different PI3K heterodimers and, using this system, we found that NS1 induces an
isoform-specific
relocation and activation of the different PI3K heterodimers. We found
that clinically relevant oncogenic mutations in both catalytic and regulatory subunits of
PI3K could mimic the effect caused by NS1, and partially rescue the loss of viral fitness
in a recombinant virus encoding a p85β-binding
deficient NS1.
