title: Reorganization of the host cell Crk(L)-PI3 kinase signaling complex by the influenza A virus NS1 protein.
abstract: The non-structural protein-1 (NS1) of influenza A virus binds the p85β subunit of phosphoinositide 3-kinase (PI3K) to induce PI3K activity in the infected cells. Some virus strains encode NS1 containing a motif that binds tightly to the SH3 domain of the cellular adapter proteins Crk and CrkL to potentiate NS1-induced PI3K activation. Here we show that this potentiation involves reorganization of the natural CrkL-p85β complex into a novel trimeric complex where NS1 serves as a bridging factor. Of note, NS1 proteins that lack the SH3 binding capacity can also associate with CrkL, but in a less stable trimeric complex mediated by p85β. The data presented here establish Crk proteins as general host cell cofactors of NS1, and show that the enhanced PI3K activation by SH3 binding-competent NS1 variants is mediated by a more efficient tethering of Crk proteins to the NS1-PI3K complex.
authors.affiliation: Department of Virology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Leena
authors.initials: L
authors.lastname: Ylösmäki
authors.affiliation: Department of Virology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Constanze
authors.initials: C
authors.lastname: Schmotz
authors.affiliation: Department of Virology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Erkko
authors.initials: E
authors.lastname: Ylösmäki
authors.affiliation: Department of Virology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. Electronic address: kalle.saksela@helsinki.fi.
authors.forename: Kalle
authors.initials: K
authors.lastname: Saksela
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D002460:Cell Line; D054884:Host-Pathogen Interactions; D006801:Humans; D009980:Influenza A virus / Q000502:physiology*; D009687:Nuclear Proteins / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D011485:Protein Binding; D055503:Protein Multimerization; D015398:Signal Transduction; D017361:Viral Nonstructural Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C082869:CRKL protein; C085820:INS1 protein, influenza virus; D009687:Nuclear Proteins; D017361:Viral Nonstructural Proteins; D058539:Phosphatidylinositol 3-Kinase
keywords: Crk; CrkL; Influenza NS1 protein; PI3K; SH3 domain; Signal transduction