The Inflammatory Kinase MAP4K4 Promotes Reactivation of Kaposi's Sarcoma Herpesvirus and Enhances the Invasiveness of Infected Endothelial Cells

Darya A. Haas, Kiran Bala, Guntram Büsche, Magdalena Weidner-Glunde, Susann Santag, Semra Kati, Silvia Gramolelli, Modester Damas, Oliver Dittrich-Breiholz, Michael Kracht, Jessica Rückert, Zoltan Varga, György Keri, Thomas F. Schulz

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Abstract

Kaposi's sarcoma (KS) is a mesenchymal tumour, which is caused by Kaposi's sarcoma herpesvirus (KSHV) and develops under inflammatory conditions. KSHV-infected endothelial spindle cells, the neoplastic cells in KS, show increased invasiveness, attributed to the elevated expression of metalloproteinases (MMPs) and cyclooxygenase-2 (COX-2). The majority of these spindle cells harbour latent KSHV genomes, while a minority undergoes lytic reactivation with subsequent production of new virions and viral or cellular chemo- and cytokines, which may promote tumour invasion and dissemination. In order to better understand KSHV pathogenesis, we investigated cellular mechanisms underlying the lytic reactivation of KSHV. Using a combination of small molecule library screening and siRNA silencing we found a STE20 kinase family member, MAP4K4, to be involved in KSHV reactivation from latency and to contribute to the invasive phenotype of KSHV-infected endothelial cells by regulating COX-2, MMP-7, and MMP-13 expression. This kinase is also highly expressed in KS spindle cells in vivo. These findings suggest that MAP4K4, a known mediator of inflammation, is involved in KS aetiology by regulating KSHV lytic reactivation, expression of MMPs and COX-2, and, thereby modulating invasiveness of KSHV-infected endothelial cells.

Original languageEnglish
Article numbere1003737
JournalPLoS Pathogens
Volume9
Issue number11
DOIs
Publication statusPublished - Nov 1 2013

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ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

Cite this

Haas, D. A., Bala, K., Büsche, G., Weidner-Glunde, M., Santag, S., Kati, S., Gramolelli, S., Damas, M., Dittrich-Breiholz, O., Kracht, M., Rückert, J., Varga, Z., Keri, G., & Schulz, T. F. (2013). The Inflammatory Kinase MAP4K4 Promotes Reactivation of Kaposi's Sarcoma Herpesvirus and Enhances the Invasiveness of Infected Endothelial Cells. PLoS Pathogens, 9(11), [e1003737]. https://doi.org/10.1371/journal.ppat.1003737