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Journal of Virology, June 2009, p. 5971-5977, Vol. 83, No. 12
0022-538X/09/$08.00+0     doi:10.1128/JVI.01667-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Interferon-Induced ISG15 Conjugation Inhibits Influenza A Virus Gene Expression and Replication in Human Cells{triangledown}

Tien-Ying Hsiang, Chen Zhao, and Robert M. Krug*

Institute for Cellular and Molecular Biology, Section of Molecular Genetics and Microbiology, University of Texas at Austin, Austin, Texas 78712

Received 5 August 2008/ Accepted 1 April 2009

The ubiquitin-like ISG15 protein, as well as its conjugating enzymes, is induced by type I interferons (IFNs). Experiments using ISG15 knockout (ISG15–/–) mice established that ISG15 and/or its conjugation inhibits the replication of influenza A virus. However, in contrast to the virus inhibition results for mice, the rates of virus replication in ISG15+/+ and ISG15–/– mouse embryo fibroblasts in tissue culture were similar. Here we focus on human tissue culture cells and on the effect of ISG15 and/or its conjugation on influenza A virus gene expression and replication in such cells. We demonstrate that IFN-induced antiviral activity against influenza A virus in human cells is significantly alleviated by inhibiting ISG15 conjugation using small interfering RNAs directed against ISG15-conjugating enzymes. IFN-induced antiviral activity against influenza A virus protein synthesis was reduced 5- to 20-fold by suppressing ISG15 conjugation. The amounts of the viral proteins that were restored by these siRNA treatments were approximately 40 to 50% of the amounts produced in cells that were not pretreated with IFN. Further, we show that ISG15 conjugation inhibits influenza A virus replication 10- to 20-fold at early times after infection in human cells. These results show that ISG15 conjugation plays a substantial role in the antiviral state induced by IFN in human cells. In contrast, we show that in mouse embryo fibroblasts ISG15 conjugation not only does not affect influenza A virus replication but also does not contribute to the IFN-induced antiviral activity against influenza A virus gene expression.

* Corresponding author. Mailing address: Institute for Cellular and Molecular Biology, MBB 2.122, 2500 Speedway, University of Texas at Austin, Austin, TX 78712. Phone: (512) 232-5563. Fax: (512) 232-5565. E-mail: rkrug{at}mail.utexas.edu

{triangledown} Published ahead of print on 8 April 2009.

Journal of Virology, June 2009, p. 5971-5977, Vol. 83, No. 12
0022-538X/09/$08.00+0     doi:10.1128/JVI.01667-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Chua, P. K., McCown, M. F., Rajyaguru, S., Kular, S., Varma, R., Symons, J., Chiu, S. S., Cammack, N., Najera, I. (2009). Modulation of alpha interferon anti-hepatitis C virus activity by ISG15. J. Gen. Virol. 90: 2929-2939 [Abstract] [Full Text]  


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