This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lenschow, D. J.
Right arrow Articles by Virgin, H. W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lenschow, D. J.
Right arrow Articles by Virgin, H. W., IV

 Previous Article  |  Next Article 

Journal of Virology, November 2005, p. 13974-13983, Vol. 79, No. 22
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.22.13974-13983.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Identification of Interferon-Stimulated Gene 15 as an Antiviral Molecule during Sindbis Virus Infection In Vivo

Deborah J. Lenschow,1,2 Nadia V. Giannakopoulos,1,2 Lacey J. Gunn,1,2 Christine Johnston,4 Andy K. O'Guin,1,2 Robert E. Schmidt,1 Beth Levine,3,4 and Herbert W. Virgin IV1,2*

Departments of Pathology,1 Immunology, Washington University School of Medicine, St. Louis, Missouri 63110,2 Division of Infectious Diseases, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9113,3 Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York 100324

Received 27 May 2005/ Accepted 12 August 2005

The innate immune response, and in particular the alpha/beta interferon (IFN-{alpha}/ß) system, plays a critical role in the control of viral infections. Interferons {alpha} and ß exert their antiviral effects through the induction of hundreds of interferon-induced (or -stimulated) genes (ISGs). While several of these ISGs have characterized antiviral functions, their actions alone do not explain all of the effects mediated by IFN-{alpha}/ß. To identify additional IFN-induced antiviral molecules, we utilized a recombinant chimeric Sindbis virus to express selected ISGs in IFN-{alpha}/ß receptor (IFN-{alpha}/ßR)–/– mice and looked for attenuation of Sindbis virus infection. Using this approach, we identified a ubiquitin homolog, interferon-stimulated gene 15 (ISG15), as having antiviral activity. ISG15 expression protected against Sindbis virus-induced lethality and decreased Sindbis virus replication in multiple organs without inhibiting the spread of virus throughout the host. We establish that, much like ubiquitin, ISG15 requires its C-terminal LRLRGG motif to form intracellular conjugates. Finally, we demonstrate that ISG15's LRLRGG motif is also required for its antiviral activity. We conclude that ISG15 can be directly antiviral.

* Corresponding author. Mailing address: Washington University School of Medicine, 660 S. Euclid Ave., Box 8118, St. Louis, MO 63110. Phone: (314) 362-9223. Fax: (314) 362-4096. E-mail: virgin{at}wustl.edu.

Journal of Virology, November 2005, p. 13974-13983, Vol. 79, No. 22
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.22.13974-13983.2005
Copyright © 2005, 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]  
  • Yin, J., Gardner, C. L., Burke, C. W., Ryman, K. D., Klimstra, W. B. (2009). Similarities and Differences in Antagonism of Neuron Alpha/Beta Interferon Responses by Venezuelan Equine Encephalitis and Sindbis Alphaviruses. J. Virol. 83: 10036-10047 [Abstract] [Full Text]  
  • Khanolkar, A., Hartwig, S. M., Haag, B. A., Meyerholz, D. K., Epping, L. L., Haring, J. S., Varga, S. M., Harty, J. T. (2009). Protective and Pathologic Roles of the Immune Response to Mouse Hepatitis Virus Type 1: Implications for Severe Acute Respiratory Syndrome. J. Virol. 83: 9258-9272 [Abstract] [Full Text]  
  • Hsiang, T.-Y., Zhao, C., Krug, R. M. (2009). Interferon-Induced ISG15 Conjugation Inhibits Influenza A Virus Gene Expression and Replication in Human Cells. J. Virol. 83: 5971-5977 [Abstract] [Full Text]  
  • Changotra, H., Jia, Y., Moore, T. N., Liu, G., Kahan, S. M., Sosnovtsev, S. V., Karst, S. M. (2009). Type I and Type II Interferons Inhibit the Translation of Murine Norovirus Proteins. J. Virol. 83: 5683-5692 [Abstract] [Full Text]  
  • Burdeinick-Kerr, R., Govindarajan, D., Griffin, D. E. (2009). Noncytolytic Clearance of Sindbis Virus Infection from Neurons by Gamma Interferon Is Dependent on Jak/Stat Signaling. J. Virol. 83: 3429-3435 [Abstract] [Full Text]  
  • Giannakopoulos, N. V., Arutyunova, E., Lai, C., Lenschow, D. J., Haas, A. L., Virgin, H. W. (2009). ISG15 Arg151 and the ISG15-Conjugating Enzyme UbE1L Are Important for Innate Immune Control of Sindbis Virus. J. Virol. 83: 1602-1610 [Abstract] [Full Text]  
  • Lai, C., Struckhoff, J. J., Schneider, J., Martinez-Sobrido, L., Wolff, T., Garcia-Sastre, A., Zhang, D.-E., Lenschow, D. J. (2009). Mice Lacking the ISG15 E1 Enzyme UbE1L Demonstrate Increased Susceptibility to both Mouse-Adapted and Non-Mouse-Adapted Influenza B Virus Infection. J. Virol. 83: 1147-1151 [Abstract] [Full Text]  
  • Kim, J.-H., Luo, J.-K., Zhang, D.-E. (2008). The Level of Hepatitis B Virus Replication Is Not Affected by Protein ISG15 Modification but Is Reduced by Inhibition of UBP43 (USP18) Expression. J. Immunol. 181: 6467-6472 [Abstract] [Full Text]  
  • Vargas-Inchaustegui, D. A., Xin, L., Soong, L. (2008). Leishmania braziliensis Infection Induces Dendritic Cell Activation, ISG15 Transcription, and the Generation of Protective Immune Responses. J. Immunol. 180: 7537-7545 [Abstract] [Full Text]  
  • Chang, Y.-G., Yan, X.-Z., Xie, Y.-Y., Gao, X.-C., Song, A.-X., Zhang, D.-E., Hu, H.-Y. (2008). Different Roles for Two Ubiquitin-like Domains of ISG15 in Protein Modification. J. Biol. Chem. 283: 13370-13377 [Abstract] [Full Text]  
  • Malakhova, O. A., Zhang, D.-E. (2008). ISG15 Inhibits Nedd4 Ubiquitin E3 Activity and Enhances the Innate Antiviral Response. J. Biol. Chem. 283: 8783-8787 [Abstract] [Full Text]  
  • Tesfay, M. Z., Yin, J., Gardner, C. L., Khoretonenko, M. V., Korneeva, N. L., Rhoads, R. E., Ryman, K. D., Klimstra, W. B. (2008). Alpha/Beta Interferon Inhibits Cap-Dependent Translation of Viral but Not Cellular mRNA by a PKR-Independent Mechanism. J. Virol. 82: 2620-2630 [Abstract] [Full Text]  
  • Okumura, A., Pitha, P. M., Harty, R. N. (2008). ISG15 inhibits Ebola VP40 VLP budding in an L-domain-dependent manner by blocking Nedd4 ligase activity. Proc. Natl. Acad. Sci. USA 105: 3974-3979 [Abstract] [Full Text]  
  • Kim, M.-J., Hwang, S.-Y., Imaizumi, T., Yoo, J.-Y. (2008). Negative Feedback Regulation of RIG-I-Mediated Antiviral Signaling by Interferon-Induced ISG15 Conjugation. J. Virol. 82: 1474-1483 [Abstract] [Full Text]  
  • Randall, R. E., Goodbourn, S. (2008). Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures. J. Gen. Virol. 89: 1-47 [Abstract] [Full Text]  
  • MacDonald, M. R., Machlin, E. S., Albin, O. R., Levy, D. E. (2007). The Zinc Finger Antiviral Protein Acts Synergistically with an Interferon-Induced Factor for Maximal Activity against Alphaviruses. J. Virol. 81: 13509-13518 [Abstract] [Full Text]  
  • Zhang, Y., Burke, C. W., Ryman, K. D., Klimstra, W. B. (2007). Identification and Characterization of Interferon-Induced Proteins That Inhibit Alphavirus Replication. J. Virol. 81: 11246-11255 [Abstract] [Full Text]  
  • Sariol, C. A., Munoz-Jordan, J. L., Abel, K., Rosado, L. C., Pantoja, P., Giavedoni, L., Rodriguez, I. V., White, L. J., Martinez, M., Arana, T., Kraiselburd, E. N. (2007). Transcriptional Activation of Interferon-Stimulated Genes but Not of Cytokine Genes after Primary Infection of Rhesus Macaques with Dengue Virus Type 1. CVI 14: 756-766 [Abstract] [Full Text]  
  • Burdeinick-Kerr, R., Wind, J., Griffin, D. E. (2007). Synergistic Roles of Antibody and Interferon in Noncytolytic Clearance of Sindbis Virus from Different Regions of the Central Nervous System. J. Virol. 81: 5628-5636 [Abstract] [Full Text]  
  • Wollmann, G., Robek, M. D., van den Pol, A. N. (2007). Variable Deficiencies in the Interferon Response Enhance Susceptibility to Vesicular Stomatitis Virus Oncolytic Actions in Glioblastoma Cells but Not in Normal Human Glial Cells. J. Virol. 81: 1479-1491 [Abstract] [Full Text]  
  • Okumura, F., Zou, W., Zhang, D.-E. (2007). ISG15 modification of the eIF4E cognate 4EHP enhances cap structure-binding activity of 4EHP. Genes Dev. 21: 255-260 [Abstract] [Full Text]  
  • Lenschow, D. J., Lai, C., Frias-Staheli, N., Giannakopoulos, N. V., Lutz, A., Wolff, T., Osiak, A., Levine, B., Schmidt, R. E., Garcia-Sastre, A., Leib, D. A., Pekosz, A., Knobeloch, K.-P., Horak, I., Virgin, H. W. IV (2007). From the cover: IFN-stimulated gene 15 functions as a critical antiviral molecule against influenza, herpes, and Sindbis viruses. Proc. Natl. Acad. Sci. USA 104: 1371-1376 [Abstract] [Full Text]  
  • Han, H., Austin, K. J, Rempel, L. A, Hansen, T. R (2006). Low blood ISG15 mRNA and progesterone levels are predictive of non-pregnant dairy cows.. J Endocrinol 191: 505-512 [Abstract] [Full Text]  
  • Kim, K. I., Yan, M., Malakhova, O., Luo, J.-K., Shen, M.-F., Zou, W., de la Torre, J. C., Zhang, D.-E. (2006). Ube1L and Protein ISGylation Are Not Essential for Alpha/Beta Interferon Signaling. Mol. Cell. Biol. 26: 472-479 [Abstract] [Full Text]  
  • Barton, E. S., Lutzke, M. L., Rochford, R., Virgin, H. W. IV (2005). Alpha/Beta Interferons Regulate Murine Gammaherpesvirus Latent Gene Expression and Reactivation from Latency. J. Virol. 79: 14149-14160 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»