Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA.
Proc Natl Acad Sci U S A. 2013 Jul 2;110(27):11139-44. doi: 10.1073/pnas.1219829110. Epub 2013 Jun 14.
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.
G 蛋白偶联受体 (GPCRs) 是一种七跨膜蛋白，可将多种细胞外信号传递穿过细胞膜。疱疹病毒基因组编码多种与病毒发病机制有关的 GPCR。卡波西肉瘤相关疱疹病毒 GPCR (kGPCR) 激活增殖途径，当在小鼠内皮细胞中表达时，足以诱导类似于人类卡波西肉瘤的血管生成肿瘤。IKKε，一种 IκB 激酶 (IKK) 相关激酶，与炎症驱动的肿瘤发生有关。我们在此报告 IKKε 对 kGPCR 肿瘤发生至关重要，并将 kGPCR 与 NF-κB 激活联系起来。使用 kGPCR 诱导的肿瘤模型，我们发现 IKKε 在卡波西肉瘤样病变中表达明显上调，并且 IKKε 的缺失消除了肿瘤形成。此外，kGPCR 与 IKKε 相互作用并激活它。激活的 IKKε 促进 NF-κB 亚基 RelA（也称为 p65）磷酸化，这与 NF-κB 激活和炎性细胞因子表达相关。在人类卡波西肉瘤中观察到 IKKε 和磷酸化 RelA 的强烈表达。最后，一种 IKKε 的激酶缺陷突变有效地阻断了 kGPCR 诱导的 NF-κB 激活和肿瘤发生。总之，我们的发现揭示了一种关键的 IKKε，它可促进病毒 GPCR 诱导的 NF-κB 激活和肿瘤发生。
