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Journal of Virology, November 2008, p. 10444-10454, Vol. 82, No. 21
0022-538X/08/$08.00+0     doi:10.1128/JVI.00833-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Binding STAT2 by the Acidic Domain of Human Cytomegalovirus IE1 Promotes Viral Growth and Is Negatively Regulated by SUMO{triangledown}

Yong Ho Huh,1 Young Eui Kim,1 Eui Tae Kim,1 Jung Jin Park,1 Moon Jung Song,2 Hua Zhu,3 Gary S. Hayward,4 and Jin-Hyun Ahn1*

Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon,1 Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea,2 Department of Microbiology and Molecular Genetics, UMDNJ-New Jersey Medical School, Newark, New Jersey,3 Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland4

Received 18 May 2008/ Accepted 5 August 2008

The human cytomegalovirus (HCMV) 72-kDa immediate-early 1 (IE1) protein is thought to modulate cellular antiviral functions impacting on promyelocytic leukemia (PML) nuclear bodies and signal transducer and activator of transcription (STAT) signaling. IE1 consists of four distinct regions: an amino-terminal region required for nuclear localization, a large central hydrophobic region responsible for PML targeting and transactivation activity, an acidic domain, and a carboxyl-terminal chromatin tethering domain. We found that the acidic domain of IE1 is required for binding to STAT2. A mutant HCMV encoding IE1({Delta}421-475) with the acidic domain deleted was generated. In mutant virus-infected cells, IE1({Delta}421-475) failed to bind to STAT2. The growth of mutant virus was only slightly delayed at a high multiplicity of infection (MOI) but was severely impaired at a low MOI with low-level accumulation of viral proteins. When cells were pretreated with beta interferon, the mutant virus showed an additional 1,000-fold reduction in viral growth, even at a high MOI, compared to the wild type. The inhibition of STAT2 loading on the target promoter upon infection was markedly reduced with mutant virus. Furthermore, sumoylation of IE1 at this acidic domain was found to abolish the activity of IE1 to bind to STAT2 and repress the interferon-stimulated genes. Our results provide genetic evidence that IE1 binding to STAT2 requires the 55-amino-acid acidic domain and promotes viral growth by interfering with interferon signaling and demonstrate that this viral activity is negatively regulated by a cellular sumoylation pathway.

* Corresponding author. Mailing address: Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, 300 Cheoncheondong Jangangu, Suwon, Gyeonggido 440-746, Republic of Korea. Phone: 82-31-299-6222. Fax: 82-31-299-6435. E-mail: jahn{at}med.skku.ac.kr

{triangledown} Published ahead of print on 13 August 2008.

Journal of Virology, November 2008, p. 10444-10454, Vol. 82, No. 21
0022-538X/08/$08.00+0     doi:10.1128/JVI.00833-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Kim, E. T., Oh, S. E., Lee, Y.-O., Gibson, W., Ahn, J.-H. (2009). Cleavage Specificity of the UL48 Deubiquitinating Protease Activity of Human Cytomegalovirus and the Growth of an Active-Site Mutant Virus in Cultured Cells. J. Virol. 83: 12046-12056 [Abstract] [Full Text]  
  • Busche, A., Marquardt, A., Bleich, A., Ghazal, P., Angulo, A., Messerle, M. (2009). The Mouse Cytomegalovirus Immediate-Early 1 Gene Is Not Required for Establishment of Latency or for Reactivation in the Lungs. J. Virol. 83: 4030-4038 [Abstract] [Full Text]  


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