Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor signalsthrough multiple pathways in endothelial cells

Kaposi's sarcoma-associated herpesvirus (KSHV; human herpesvirus 8) encodes a chemokine-like G protein-coupled receptor (KSHV-GPCR) that is implicated in the pathogenesis of Kaposi's sarcoma (KS). Since endothelial cells appe ar to be targets for the virus, we developed an in vitro mouse lung endothe lial cell model in which KSHV-GPCR is stably expressed and KSHV-GPCR signal ing was studied. In mouse lung endothelial cells: 1) HSHV-GPCR does not exh ibit basal signaling through the phosphoinositide-specific phospholipase C pathway but inositol phosphate production is stimulated by growth-related o ncogene a (Gro-alpha) via a pertussis toxin (PTX) -insensitive pathway; 2) KSHV-GPCR signals basally through a PTX-sensitive pathway leading to a lowe ring of intracellular cAMP level that can be lowered further by Gro alpha a nd increased by interferon gamma -inducible protein 10; 3) KSHV-GPCR stimul ates phosphatidylinositol 3-kinase via a PTX-insensitive mechanism; and 4) KSHV-GPCR activates nuclear factor-kappaB (NF-kappaB) by a PTX-sensitive GB gamma subunit-mediated pathway. These data show that KSHV-GPCR couples to at least two G proteins and initiates signaling via at least three cascades in endothelial cells thereby increasing the complexity of regulation of en dothelial cell function by KSHV-GPCR that may occur during viral infection.