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

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. © 2013 haas et al.