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.

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Available from: Martina Schroeder, Sep 01, 2015
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    • "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). "
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    • "Several DDX proteins have been implicated in innate immunity in which they function either RNA sensors such as RIG-I (retinoic acidinduce gene-I) and MDA5 (melanoma differentiation associated gene 5) or signaling molecules such as DDX3 [17] [22]. RIG-I-like receptors (RLRs), including RIG-I, MDA5 and LGP2 (laboratory of genetics and physiology 2/DExH box polypeptide 58), belong to a class of PRRs for viral PAMPs (pathogen-associated molecular patterns ) in the cytoplasm. "
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    • "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. "
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