title: IKK epsilon kinase is crucial for viral G protein-coupled receptor tumorigenesis.
abstract: 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. IKKε, an IκB kinase (IKK)-related kinase, is implicated in inflammation-driven tumorigenesis. We report here that IKKε is critically required for kGPCR tumorigenesis and links kGPCR to NF-κB activation. Using kGPCR-induced tumor models, we found that IKKε expression was drastically up-regulated in Kaposi sarcoma-like lesions and that loss of IKKε abolished tumor formation. Moreover, kGPCR interacted with and activated IKKε. Activated IKKε promoted NF-κB subunit RelA (also known as p65) phosphorylation, which correlated with NF-κB activation and inflammatory cytokine expression. The robust expression of IKKε and phosphorylated RelA was observed in human Kaposi sarcoma. Finally, a kinase-defective mutant of IKKε effectively abrogated NF-κB activation and tumorigenesis induced by kGPCR. Collectively, our findings uncover a critical IKKε in promoting NF-κB activation and tumorigenesis induced by a viral GPCR.
authors.affiliation: Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.forename: Xiaolu
authors.initials: X
authors.lastname: Lu
authors.forename: Lining
authors.initials: L
authors.lastname: Zhu
authors.forename: Yan
authors.initials: Y
authors.lastname: Shen
authors.forename: Shylet
authors.initials: S
authors.lastname: Chengedza
authors.forename: Hao
authors.initials: H
authors.lastname: Feng
authors.forename: Laiyee
authors.initials: L
authors.lastname: Wang
authors.forename: Jae U
authors.initials: JU
authors.lastname: Jung
authors.forename: J Silvio
authors.initials: JS
authors.lastname: Gutkind
authors.forename: Julio S
authors.initials: JS
authors.lastname: Gutkind
authors.forename: Pinghui
authors.initials: P
authors.lastname: Feng
mesh_terms: D000818:Animals; D004789:Enzyme Activation; D057809:HEK293 Cells; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D054884:Host-Pathogen Interactions / Q000235:genetics; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D019899:Paracrine Communication / Q000235:genetics; D019707:Receptors, Chemokine / Q000378:metabolism*; D012514:Sarcoma, Kaposi / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D014183:Transplantation, Heterologous; D015854:Up-Regulation / Q000235:genetics; D014764:Viral Proteins / Q000378:metabolism*
chemical_list: C115448:G protein-coupled receptor, Human herpesvirus 8; D019707:Receptors, Chemokine; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D014764:Viral Proteins; D051550:I-kappa B Kinase
keywords: inflammation associated; sarcomagenesis