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Journal of Virology, June 2007, p. 5995-6006, Vol. 81, No. 11
0022-538X/07/$08.00+0     doi:10.1128/JVI.01714-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Nuclear and Nucleolar Targeting of Influenza A Virus NS1 Protein: Striking Differences between Different Virus Subtypes{triangledown}

Krister Melén,1* Leena Kinnunen,2 Riku Fagerlund,1 Niina Ikonen,1 Karen Y. Twu,3 Robert M. Krug,3 and Ilkka Julkunen1

Departments of Viral Diseases and Immunology,1 Epidemiology and Health Promotion, National Public Health Institute, FIN-00300, Helsinki, Finland,2 Section of Molecular Genetics and Microbiology, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, Texas 787123

Received 8 August 2006/ Accepted 9 March 2007

Influenza A virus nonstructural protein 1 (NS1A protein) is a virulence factor which is targeted into the nucleus. It is a multifunctional protein that inhibits host cell pre-mRNA processing and counteracts host cell antiviral responses. We show that the NS1A protein can interact with all six human importin {alpha} isoforms, indicating that the nuclear translocation of NS1A protein is mediated by the classical importin {alpha}/ß pathway. The NS1A protein of the H1N1 (WSN/33) virus has only one N-terminal arginine- or lysine-rich nuclear localization signal (NLS1), whereas the NS1A protein of the H3N2 subtype (Udorn/72) virus also has a second C-terminal NLS (NLS2). NLS1 is mapped to residues 35 to 41, which also function in the double-stranded RNA-binding activity of the NS1A protein. NLS2 was created by a 7-amino-acid C-terminal extension (residues 231 to 237) that became prevalent among human influenza A virus types isolated between the years 1950 to 1987. NLS2 includes basic amino acids at positions 219, 220, 224, 229, 231, and 232. Surprisingly, NLS2 also forms a functional nucleolar localization signal NoLS, a function that was retained in H3N2 type virus NS1A proteins even without the C-terminal extension. It is likely that the evolutionarily well-conserved nucleolar targeting function of NS1A protein plays a role in the pathogenesis of influenza A virus.

* Corresponding author. Mailing address: Department of Viral Diseases and Immunology, National Public Health Institute, Mannerheimintie 166, FIN-00300, Helsinki, Finland. Phone: 358 9 47448879. Fax: 358 9 47448355. E-mail: krister.melen{at}ktl.fi

{triangledown} Published ahead of print on 21 March 2007.

Journal of Virology, June 2007, p. 5995-6006, Vol. 81, No. 11
0022-538X/07/$08.00+0     doi:10.1128/JVI.01714-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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