Article

Viral targeting of DEAD box protein 3 reveals its role in TBK1/IKKepsilon-mediated IRF activation

Viral Immune Evasion Group, School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland.
The EMBO Journal (Impact Factor: 10.75). 08/2008; 27(15):2147-57. DOI: 10.1038/emboj.2008.143
Source: PubMed

ABSTRACT Viruses are detected by different classes of pattern recognition receptors (PRRs), such as Toll-like receptors and RIG-like helicases. Engagement of PRRs leads to activation of interferon (IFN)-regulatory factor 3 (IRF3) and IRF7 through IKKepsilon and TBK1 and consequently IFN-beta induction. Vaccinia virus (VACV) encodes proteins that manipulate host signalling, sometimes by targeting uncharacterised proteins. Here, we describe a novel VACV protein, K7, which can inhibit PRR-induced IFN-beta induction by preventing TBK1/IKKepsilon-mediated IRF activation. We identified DEAD box protein 3 (DDX3) as a host target of K7. Expression of DDX3 enhanced Ifnb promoter induction by TBK1/IKKepsilon, whereas knockdown of DDX3 inhibited this, and virus- or dsRNA-induced IRF3 activation. Further, dominant-negative DDX3 inhibited virus-, dsRNA- and cytosolic DNA-stimulated Ccl5 promoter induction, which is also TBK1/IKKepsilon dependent. Both K7 binding and enhancement of Ifnb induction mapped to the N-terminus of DDX3. Furthermore, virus infection induced an association between DDX3 and IKKepsilon. Therefore, this study shows for the first time the involvement of a DEAD box helicase in TBK1/IKKepsilon-mediated IRF activation and Ifnb promoter induction.

Download full-text

Full-text

Available from: Martina Schroeder, Aug 01, 2015
1 Follower
 · 
199 Views
  • Source
    • "Approximately 60 genes encode DDX helicases in the human genome. Bowie and colleagues first reported that a member of the DDX superfamily is involved in RIG-I signaling (Schrö der et al., 2008; Soulat et al., 2008). Subsequently, other studies have shown that DDX superfamily members such as DDX3, DHX29, DHX36, and DDX60 are involved in RIG-I-dependent type I IFN production in response to viral RNA and DNA (Desmet and Ishii, 2012; Sugimoto et al., 2014; Yoo et al., 2014). "
    [Show abstract] [Hide abstract]
    ABSTRACT: RIG-I-mediated type I interferon (IFN) production and nuclease-mediated viral RNA degradation are essential for antiviral innate immune responses. DDX60 is an IFN-inducible cytoplasmic helicase. Here, we report that DDX60 is a sentinel for both RIG-I activation and viral RNA degradation. We show that DDX60 is an upstream factor of RIG-I that activates RIG-I signaling in a ligand-specific manner. DDX60 knockout attenuates RIG-I signaling and significantly reduces virus-induced type I IFN production in vivo. In addition, we show that DDX60 is involved in RIG-I-independent viral RNA degradation. DDX60 and RIG-I adaptor MAVS double-knockout mice reveal a role for DDX60-dependent RNA degradation in antiviral responses. Several viruses induced DDX60 phosphorylation via epidermal growth factor receptor (EGFR), leading to attenuation of the DDX60 antiviral activities. Our results define DDX60 as a sentinel for cytoplasmic antiviral response, which is counteracted by virus-mediated EGF receptor activation. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 05/2015; 12(8). DOI:10.1016/j.celrep.2015.04.047 · 7.21 Impact Factor
  • Source
    • "More recently, Oshiumi et al. demonstrated an interaction between DDX3 and IPS1 and suggested that DDX3 might directly bind to vesicular stomatitis virus (VSV) RNA in conjunction with RIG-I and MDA5 to enhance the IFN-I response, supporting a regulatory role of DDX3 in the RLR pathway [72] (Fig. 2B). Also noted, DDX3 is targeted by vaccinia virus protein K7 [70] and HCV core protein [73] to abrogate DDX3- enhanced IPS-1 signaling. Collectively, these findings underscore the relevance of DDX3 in efficient sensing of pathogen-derived nucleic acids. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Environmental stresses threatening cell homeostasis trigger various cellular responses ranging from the activation of survival pathways to eliciting programmed cell death. Cellular stress response highly depends on the nature and level of the insult as well as the cell type. Notably, the interplay among all these responses will ultimately determine the fate of the stressed cell. Human DExD/H RNA helicases are ubiquitous molecular motors rearranging RNA secondary structure in an ATP-dependent fashion. These highly conserved enzymes participate in nearly all aspects of cellular process involving RNA metabolism. Although numerous functions of DExD/H RNA helicases are well documented, their importance in stress response is only just becoming evident. This review outlines our current knowledge on major mechanistic themes of human DExD/H RNA helicases in response to stressful stimuli, especially on emerging molecular models for the functional roles of these enzymes in the stress survival regulation.
    Clinica Chimica Acta 05/2014; 436. DOI:10.1016/j.cca.2014.05.003 · 2.82 Impact Factor
  • Source
    • "IFI16/p204 has been identified as an intracellular DNA sensor to induce type I IFN production [59]. IFI16/p204 binds cytosolic dsDNA and induces type I IFNs and inflammatory cytokines through STING [75] [76]. RNAi knockdown of IFI16/ p204 in human and murine monocytic cell lines abrogates the activation of IRF3 and NF-κB and subsequent induction of IFN-β and inflammatory cytokines [59]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Herpes simplex viruses (HSV) are human pathogens that establish lytic and latent infections. Reactivation from latency occurs intermittently, which represents a life-long source of recurrent infection. In this complex process, HSV triggers and neutralizes innate immunity. Therefore, a dynamic equilibrium between HSV and the innate immune system determines the outcome of viral infection. Detection of HSV involves pathogen recognition receptors which include Toll-like receptors (TLRs), retinoic acid-inducible gene I (RIG-I) like receptors, and cytosolic DNA sensors. Moreover, innate components or pathways exist to sense membrane fusion upon viral entry into host cells. Consequently, this surveillance network activates downstream transcription factors, leading to the induction of type I interferon (IFN) and inflammatory cytokines. Not surprisingly, with the capacity to establish chronic infection HSV has evolved strategies that modulate or evade innate immunity. In this review, we describe recent advances pertinent to the interplay of HSV and the induction of innate immunity mediated by pathogen recognition receptors or pathways.
    Journal of Molecular Biology 11/2013; 426(6). DOI:10.1016/j.jmb.2013.11.012 · 4.33 Impact Factor
Show more