Avian and 1918 Spanish influenza a virus NS1 proteins bind to Crk/CrkL Src homology 3 domains to activate host cell signaling

Leena S Heikkinen, Arunas Kazlauskas, Krister Melen, Ralf Wagner, Thedi Ziegler, Ilkka Julkunen, Kalle Saksela

    Tutkimustuotos: ArtikkelijulkaisuArtikkeliTieteellinenvertaisarvioitu

    Kuvaus

    NS1 (nonstructural protein 1) is an important virulence factor of the influenza A virus. We observed that NS1 proteins of the 1918 pandemic virus (A/ Brevig Mission/ 1/ 18) and many avian influenza A viruses contain a consensus Src homology 3 (SH3) domain-binding motif. Screening of a comprehensive human SH3 phage library revealed the N-terminal SH3 of Crk and CrkL as the preferred binding partners. Studies with recombinant proteins confirmed avid binding of NS1 proteins of the 1918 virus and a representative avian H7N3 strain to Crk/ CrkL SH3 but not to other SH3 domains tested, including p85 alpha and p85 beta. Endogenous CrkL readily co-precipitated NS1 from cells infected with the H7N3 virus. In transfected cells association with CrkL was observed for NS1 of the 1918 and H7N3 viruses but not A/ Udorn/ 72 or A/WSN/ 33 NS1 lacking this sequence motif. SH3 binding was dispensable for suppression of interferoninduced gene expression by NS1 but was associated with enhanced phosphatidylinositol 3-kinase signaling, as evidenced by increased Akt phosphorylation. Thus, the Spanish Flu virus resembles avian influenza A viruses in its ability to recruit Crk/CrkL to modulate host cell signaling.
    Alkuperäiskielienglanti
    LehtiJournal of Biological Chemistry
    Vuosikerta283
    Numero9
    Sivut5719-5727
    Sivumäärä9
    ISSN0021-9258
    DOI - pysyväislinkit
    TilaJulkaistu - 2008
    OKM-julkaisutyyppiA1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä, vertaisarvioitu

    Lainaa tätä

    Heikkinen, Leena S ; Kazlauskas, Arunas ; Melen, Krister ; Wagner, Ralf ; Ziegler, Thedi ; Julkunen, Ilkka ; Saksela, Kalle. / Avian and 1918 Spanish influenza a virus NS1 proteins bind to Crk/CrkL Src homology 3 domains to activate host cell signaling. Julkaisussa: Journal of Biological Chemistry. 2008 ; Vuosikerta 283, Nro 9. Sivut 5719-5727.
    @article{1c532a4b76ee4ae4aa3e374623f62a3b,
    title = "Avian and 1918 Spanish influenza a virus NS1 proteins bind to Crk/CrkL Src homology 3 domains to activate host cell signaling",
    abstract = "NS1 (nonstructural protein 1) is an important virulence factor of the influenza A virus. We observed that NS1 proteins of the 1918 pandemic virus (A/ Brevig Mission/ 1/ 18) and many avian influenza A viruses contain a consensus Src homology 3 (SH3) domain-binding motif. Screening of a comprehensive human SH3 phage library revealed the N-terminal SH3 of Crk and CrkL as the preferred binding partners. Studies with recombinant proteins confirmed avid binding of NS1 proteins of the 1918 virus and a representative avian H7N3 strain to Crk/ CrkL SH3 but not to other SH3 domains tested, including p85 alpha and p85 beta. Endogenous CrkL readily co-precipitated NS1 from cells infected with the H7N3 virus. In transfected cells association with CrkL was observed for NS1 of the 1918 and H7N3 viruses but not A/ Udorn/ 72 or A/WSN/ 33 NS1 lacking this sequence motif. SH3 binding was dispensable for suppression of interferoninduced gene expression by NS1 but was associated with enhanced phosphatidylinositol 3-kinase signaling, as evidenced by increased Akt phosphorylation. Thus, the Spanish Flu virus resembles avian influenza A viruses in its ability to recruit Crk/CrkL to modulate host cell signaling.",
    author = "Heikkinen, {Leena S} and Arunas Kazlauskas and Krister Melen and Ralf Wagner and Thedi Ziegler and Ilkka Julkunen and Kalle Saksela",
    year = "2008",
    doi = "10.1074/jbc.M707195200",
    language = "English",
    volume = "283",
    pages = "5719--5727",
    journal = "Journal of Biological Chemistry",
    issn = "0021-9258",
    publisher = "American Society for Biochemistry and Molecular Biology",
    number = "9",

    }

    Avian and 1918 Spanish influenza a virus NS1 proteins bind to Crk/CrkL Src homology 3 domains to activate host cell signaling. / Heikkinen, Leena S; Kazlauskas, Arunas; Melen, Krister; Wagner, Ralf; Ziegler, Thedi; Julkunen, Ilkka; Saksela, Kalle.

    julkaisussa: Journal of Biological Chemistry, Vuosikerta 283, Nro 9, 2008, s. 5719-5727.

    Tutkimustuotos: ArtikkelijulkaisuArtikkeliTieteellinenvertaisarvioitu

    TY - JOUR

    T1 - Avian and 1918 Spanish influenza a virus NS1 proteins bind to Crk/CrkL Src homology 3 domains to activate host cell signaling

    AU - Heikkinen, Leena S

    AU - Kazlauskas, Arunas

    AU - Melen, Krister

    AU - Wagner, Ralf

    AU - Ziegler, Thedi

    AU - Julkunen, Ilkka

    AU - Saksela, Kalle

    PY - 2008

    Y1 - 2008

    N2 - NS1 (nonstructural protein 1) is an important virulence factor of the influenza A virus. We observed that NS1 proteins of the 1918 pandemic virus (A/ Brevig Mission/ 1/ 18) and many avian influenza A viruses contain a consensus Src homology 3 (SH3) domain-binding motif. Screening of a comprehensive human SH3 phage library revealed the N-terminal SH3 of Crk and CrkL as the preferred binding partners. Studies with recombinant proteins confirmed avid binding of NS1 proteins of the 1918 virus and a representative avian H7N3 strain to Crk/ CrkL SH3 but not to other SH3 domains tested, including p85 alpha and p85 beta. Endogenous CrkL readily co-precipitated NS1 from cells infected with the H7N3 virus. In transfected cells association with CrkL was observed for NS1 of the 1918 and H7N3 viruses but not A/ Udorn/ 72 or A/WSN/ 33 NS1 lacking this sequence motif. SH3 binding was dispensable for suppression of interferoninduced gene expression by NS1 but was associated with enhanced phosphatidylinositol 3-kinase signaling, as evidenced by increased Akt phosphorylation. Thus, the Spanish Flu virus resembles avian influenza A viruses in its ability to recruit Crk/CrkL to modulate host cell signaling.

    AB - NS1 (nonstructural protein 1) is an important virulence factor of the influenza A virus. We observed that NS1 proteins of the 1918 pandemic virus (A/ Brevig Mission/ 1/ 18) and many avian influenza A viruses contain a consensus Src homology 3 (SH3) domain-binding motif. Screening of a comprehensive human SH3 phage library revealed the N-terminal SH3 of Crk and CrkL as the preferred binding partners. Studies with recombinant proteins confirmed avid binding of NS1 proteins of the 1918 virus and a representative avian H7N3 strain to Crk/ CrkL SH3 but not to other SH3 domains tested, including p85 alpha and p85 beta. Endogenous CrkL readily co-precipitated NS1 from cells infected with the H7N3 virus. In transfected cells association with CrkL was observed for NS1 of the 1918 and H7N3 viruses but not A/ Udorn/ 72 or A/WSN/ 33 NS1 lacking this sequence motif. SH3 binding was dispensable for suppression of interferoninduced gene expression by NS1 but was associated with enhanced phosphatidylinositol 3-kinase signaling, as evidenced by increased Akt phosphorylation. Thus, the Spanish Flu virus resembles avian influenza A viruses in its ability to recruit Crk/CrkL to modulate host cell signaling.

    U2 - 10.1074/jbc.M707195200

    DO - 10.1074/jbc.M707195200

    M3 - Article

    VL - 283

    SP - 5719

    EP - 5727

    JO - Journal of Biological Chemistry

    JF - Journal of Biological Chemistry

    SN - 0021-9258

    IS - 9

    ER -