Abstract
Kaposi’s sarcoma (KS), caused by Kaposi’s sarcoma herpesvirus (KSHV), is a highly vascularised tumour of endothelial origin. KSHV infected endothelial cells show increased invasiveness and angiogenesis. Here, we report that the KSHV K15 protein, which we showed previously to contribute to KSHV-induced angiogenesis, is also involved in KSHV-mediated invasiveness in a PLCγ1-dependent manner. We identified βPIX, GIT1 and cdc42, downstream effectors of PLCγ1 in cell migration, as K15 interacting partners and as contributors to KSHV-triggered invasiveness. We mapped the interaction between PLCγ1, PLCγ2 and their individual domains with two K15 alleles, P and M. We found that the PLCγ2 cSH2 domain, by binding to K15P, can be used as dominant negative inhibitor of the K15P-PLCγ1 interaction, K15P-dependent PLCγ1 phosphorylation, NFAT-dependent promoter activation and the increased invasiveness and angiogenic properties of KSHV infected endothelial cells. We increased the binding of the PLCγ2 cSH2 domain for K15P by substituting two amino acids, thereby creating an improved dominant negative inhibitor of the K15P-dependent PLCγ1 activation. Taken together, these results demonstrate a necessary role of K15 in the increased invasiveness and angiogenesis of KSHV infected endothelial cells and suggest the K15-PLCγ1 interaction as a possible new target for inhibiting the angiogenic and invasive properties of KSHV.
Highlights
Kaposi’s Sarcoma Herpesvirus (KSHV), known as human herpesvirus 8 (HHV-8), was first identified in Kaposi’s sarcoma (KS) tissues by representational difference analysis [1,2]
Kaposi’s Sarcoma (KS), etiologically linked to Kaposi’s sarcoma herpesvirus (KSHV), is a tumour of endothelial origin characterised by angiogenesis and invasiveness
We report that the KSHV protein K15, which increases the angiogenicity of endothelial cells, contributes to KSHV-mediated invasiveness by the recruitment and activation of PLOS Pathogens | DOI:10.1371/journal.ppat
Summary
Kaposi’s Sarcoma Herpesvirus (KSHV), known as human herpesvirus 8 (HHV-8), was first identified in Kaposi’s sarcoma (KS) tissues by representational difference analysis [1,2]. The majority of KSHV infected endothelial cells in KS tissue harbour the virus in a latent phase, a small population undergoes lytic (productive) reactivation [10]. Among the KSHV-encoded proteins that possess angiogenic and invasive properties are the latency associated nuclear antigen 1 (LANA1), the viral homolog of G-protein coupled receptor (vGPCR, a constitutively active IL8 receptor), the viral homolog of interleukin 6 (vIL6), two viral chemokine homologs, vCCL1 and 2, as well as the K1 protein [12,14,15,16] In this context, we recently reported that the KSHV K15 protein contributes to KSHV-mediated angiogenesis [17]
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