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

Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 06/2013; 110(30). DOI: 10.1073/pnas.1219829110
Source: PubMed


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.

14 Reads
  • [Show abstract] [Hide abstract]
    ABSTRACT: All herpesviruses share a remarkable propensity to establish latent infection. Human Kaposi's sarcoma-associated herpesvirus (KSHV) effectively enters latency after de novo infection, suggesting that KSHV has evolved with strategies to facilitate latent infection. NF-κB activation is imperative for latent infection of gammaherpesviruses. However, how NF-κB is activated during de novo herpesvirus infection is not fully understood. Here, we report that KSHV infection activates the inhibitor of κB kinase β (IKKβ) and the IKK-related kinase epsilon (IKKε) to enable host NF-κB activation and KSHV latent infection. Specifically, KSHV infection activated IKKβ and IKKε that were crucial for latent infection. Knockdown of IKKβ and IKKε caused aberrant lytic gene expression and impaired KSHV latent infection. Biochemical and genetic experiments identified RelA as a key player downstream of IKKβ and IKKε. Remarkably, IKKβ and IKKε were essential for phosphorylation of S536 and S468 of RelA, respectively. Phosphorylation of RelA S536 was required for phosphorylation of S468, which activated NF-κB and promoted KSHV latent infection. Expression of the phosphorylation-resistant RelA S536A increased KSHV lytic gene expression and impaired latent infection. Our findings uncover a scheme wherein NF-κB activation is coordinated by IKKβ and IKKε, which sequentially phosphorylate RelA in a site-specific manner to enable latent infection after KSHV de novo infection.
    Journal of Virology 10/2013; 88(1). DOI:10.1128/JVI.01716-13 · 4.44 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Approximately 10.8% of human cancers are associated with infection by an oncogenic virus. These viruses include human papillomavirus (HPV), Epstein–Barr virus (EBV), Merkel cell polyomavirus (MCV), human T-cell leukemia virus 1 (HTLV-1), Kaposi's sarcoma-associated herpesvirus (KSHV), hepatitis C virus (HCV) and hepatitis B virus (HBV). These oncogenic viruses, with the exception of HCV, require the host RNA splicing machinery in order to exercise their oncogenic activities, a strategy that allows the viruses to efficiently export and stabilize viral RNA and to produce spliced RNA isoforms from a bicistronic or polycistronic RNA transcript for efficient protein translation. Infection with a tumor virus affects the expression of host genes, including host RNA splicing factors, which play a key role in regulating viral RNA splicing of oncogene transcripts. A current prospective focus is to explore how alternative RNA splicing and the expression of viral oncogenes take place in a cell- or tissue-specific manner in virus-induced human carcinogenesis.
    Emerging Microbes and Infections 09/2014; 3(9). DOI:10.1038/emi.2014.62 · 2.26 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Herpesviruses are an ancient group which have exploited gene capture of multiple cellular modulators of the immune response. Viral homologues of 7 transmembrane receptors (v7TMRs) are a consistent feature of beta- and gammaherpesviruses; the majority of the v7TMRs are homologous to cellular chemokine receptors (CKRs). Conserved families of v7TMRs distinguish between beta- versus gammaherpesviruses; furthermore, significant divisions within these subfamilies, such as between genera of the gammaherpesviruses or between the primate and rodent cytomegaloviruses, coincide with specific v7TMR gene families. Divergence of functional properties between the viral 7TMR and their cellular counterparts is likely, therefore, to reflect adaptation supporting various aspects of the viral lifecycle with concomitant effects upon viral pathogenesis. Consistent with their long evolutionary history, the v7TMRs have acquired a range of distinctive characteristics. This chapter reviews key features of the v7TMRs which are likely to impact upon their functional roles: trafficking properties, ligand specificity, and signaling capacity. Rapid, constitutive endocytosis, reminiscent of cellular "scavenger" receptors, may provide a mechanism for immune evasion, or alternatively relate to virion assembly, including incorporation of v7TMRs within the virion envelope. Some v7TMRs display relatively broad chemokine-binding specificity, whereas others remain "orphan" and may be completely independent of ligand activation. Indeed, many of the v7TMRs have been shown to signal constitutively, associated in some cases with notable divergence of highly conserved regulatory elements such as the "DRY" motif of TMIII. The availability of rodent models for v7TMR functional studies has provided evidence for important biological roles, including cellular transformation, tissue tropism, and viral persistence. Recent studies addressing signaling pathways critical to these phenotypes will be discussed, with reference to both beta- and gammaherpesviruses. © 2015 Elsevier Inc. All rights reserved.
    Progress in molecular biology and translational science 01/2015; 129C:353-393. DOI:10.1016/bs.pmbts.2014.10.010 · 3.49 Impact Factor
Show more