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Kaposi's Sarcoma-Associated Herpesvirus K-bZIP Represses Gene Transcription via SUMO Modification

Department of Biological Chemistry, University of California—Davis (UC Davis) School of Medicine, UC Davis Cancer Center, Research Building III, Room 2400, 4645 2nd Avenue, Sacramento, California 95817,¹ Center for Comparative Medicine and Department of Pathology, UC Davis, 1 Sheilds Avenue, Davis, California 95616,⁴ Department of Cardiology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe 449, Houston, Texas 77030,² Virology Division, Department of Microbiology and Molecular Genetics and Tumors, New England Primate Research Center, Harvard Medical School, Southborough, Massachusetts 01772³

Received 6 January 2005/ Accepted 22 April 2005

Kaposi's sarcoma-associated herpesvirus (KSHV) is a human gammaherpesvirus implicated in AIDS-related neoplasms. Previously, we demonstrated that the early lytic gene product K-bZIP is a transcriptional repressor that affects a subset of viral gene transcriptions mediated by the viral transactivator K-Rta (Y. Izumiya et al. J. Virol. 77:1441-1451, 2003). Sumoylation has emerged as an important posttranslational modification that affects the location and function of cellular and viral proteins and also plays a significant role in transcriptional repression along with Ubc9, the E2 SUMO conjugation enzyme. Here, we provide evidence that K-bZIP is sumoylated at the lysine 158 residue and associates with Ubc9 both in a cell-free system and in virus-infected BCBL-1 cells. Reporter assays showed that the expression of SUMO-specific protease 1 attenuated the transcriptional repression activity of K-bZIP. The expression of a K-bZIPK158R mutant, which was no longer sumoylated, exhibited the reduced transcriptional repression activity. This indicates that sumoylation plays an important part in the transcriptional repression activity of K-bZIP. Finally, chromatin immunoprecipitation experiments demonstrated that K-bZIP interacts with and recruits Ubc9 to specific KSHV promoters. Thus, our data indicate that K-bZIP is a SUMO adaptor, which recruits Ubc9 to specific viral target promoters, thereby exerting its transcriptional repression activity.

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