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Journal of Virology, January 2007, p. 42-58, Vol. 81, No. 1
0022-538X/07/$08.00+0     doi:10.1128/JVI.00648-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Modulation of Host Gene Expression by the K15 Protein of Kaposi's Sarcoma-Associated Herpesvirus{triangledown}

Melanie M. Brinkmann,1,{dagger} Marcel Pietrek,1 Oliver Dittrich-Breiholz,2 Michael Kracht,2 and Thomas F. Schulz1*

Institut für Virologie, Medizinische Hochschule Hannover, Carl-Neuberg Strasse 1, D-30625 Hannover, Germany,1 Institut für Pharmakologie, Medizinische Hochschule Hannover, Carl-Neuberg Strasse 1, D-30625 Hannover, Germany2

Received 30 March 2006/ Accepted 27 September 2006

Kaposi's sarcoma-associated herpesvirus (KSHV) contains several open reading frames (ORFs) encoding proteins capable of initiating signal transduction pathways. Among them is the K15 ORF, which consists of eight exons encoding a protein with 12 predicted transmembrane domains and a cytoplasmic C terminus. When transiently expressed, the 8-exon K15 transcript gives rise to a protein with an apparent molecular mass of 45 kDa. K15 interacts with cellular proteins, TRAF (tumor necrosis factor receptor-associated factor) and Src kinases, and activates AP-1, NF-{kappa}B, and the mitogen-activated protein kinases (MAPKs) c-jun-N-terminal kinase and extracellular signal-regulated kinase. This signaling activity of K15 is related to phosphorylation of Y481 of the K15 SH2-B motif Y481EEV. In this study we demonstrate the expression of an endogenous 45-kDa K15 protein in KSHV BAC36-infected epithelial cells. This endogenous K15 protein shows the same intracellular localization as transiently expressed K15, and expression kinetic studies suggest it to be a lytic gene. We have further determined the downstream target genes of K15 signaling using DNA oligonucleotide microarrays. We demonstrate that K15 is capable of inducing expression of multiple cytokines and chemokines, including interleukin-8 (IL-8), IL-6, CCL20, CCL2, CXCL3, and IL-1{alpha}/ß, as well as expression of Dscr1 and Cox-2. In epithelial cells, K15-induced upregulation of most genes was dependent on phosphorylation of Y481, whereas in endothelial cells mutation of Y481 did not result in a complete loss of Dscr1 and Cox-2 expression and NFAT-activity. Our study establishes K15 as one of the KSHV lytic genes that are inducing expression of multiple cytokines, which have been shown to play an important role in KSHV-associated pathogenesis.

* Corresponding author. Mailing address: Institut für Virologie, Medizinische Hochschule Hannover, Carl-Neuberg Str. 1, D-30625 Hannover, Germany. Phone: 49 511 532 6736. Fax: 49 511 532 8736. E-mail: schulz.thomas{at}mh-hannover.de.

{triangledown} Published ahead of print on 18 October 2006.

{dagger} Present address: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142.

Journal of Virology, January 2007, p. 42-58, Vol. 81, No. 1
0022-538X/07/$08.00+0     doi:10.1128/JVI.00648-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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