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J. Biol. Chem., Vol. 283, Issue 9, 5719-5727, February 29, 2008

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Avian and 1918 Spanish Influenza A Virus NS1 Proteins Bind to Crk/CrkL Src Homology 3 Domains to Activate Host Cell Signaling^*

Leena S. Heikkinen¹, Arunas Kazlauskas, Krister Melén, Ralf Wagner^¶, Thedi Ziegler, Ilkka Julkunen, and Kalle Saksela²

From the Department of Virology, Haartman Institute, University of Helsinki and Helsinki University Central Hospital, Haartmaninkatu 3 (POB 21), FIN-00014, Helsinki, Finland, the Department of Viral Diseases and Immunology, National Public Health Institute, FIN-00300, Helsinki, Finland, and ^¶Institute of Medical Microbiology and Hygiene, University of Regensburg, Franz-Josef-Strausse Allee 11, Regensburg D-93053, Germany

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 and p85β. 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 interferon-induced 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.

Received for publication, August 28, 2007 , and in revised form, December 27, 2007.

^* This work was supported in part by grants (to K. S. and I. J.) from the Academy of Finland and the Sigrid Juselius Foundation and a grant from the Helsinki University Hospital (to K. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by the Helsinki Biomedical Graduate School.

² To whom correspondence should be addressed. Tel.: 358-9-191-26770; Fax: 358-9-191-26491; E-mail: kalle.saksela{at}helsinki.fi.

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