IKK epsilon kinase is crucial for viral G protein-coupled receptor tumorigenesis

G protein-coupled receptors (GPCRs) are seven-transmembrane proteins that transmit diverse extracellular signals across a membrane. Herpesvirus genomes encode multiple GPCRs implicated in viral pathogenesis. Kaposi sarcoma-associated herpesvirus GPCR (kGPCR) activates proliferative pathways and, when expressed in endothelium in mice, sufficiently induces angiogenic tumor resembling human Kaposi's sarcoma. IKK epsilon, an I kappa B kinase (IKK)-related kinase, is implicated in inflammation-driven tumorigenesis. We report here that IKK epsilon is critically required for kGPCR tumorigenesis and links kGPCR to NF-kappa B activation. Using kGPCR-induced tumor models, we found that IKK epsilon expression was drastically up-regulated in Kaposi sarcoma-like lesions and that loss of IKK epsilon abolished tumor formation. Moreover, kGPCR interacted with and activated IKK epsilon. Activated IKK epsilon promoted NF-kappa B subunit RelA (also known as p65) phosphorylation, which correlated with NF-kappa B activation and inflammatory cytokine expression. The robust expression of IKK epsilon and phosphorylated RelA was observed in human Kaposi sarcoma. Finally, a kinase-defective mutant of IKK epsilon effectively abrogated NF-kappa B activation and tumorigenesis induced by kGPCR. Collectively, our findings uncover a critical IKK epsilon in promoting NF-kappa B activation and tumorigenesis induced by a viral GPCR.