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: 10.43). 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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    • "In virus infections, opposing effects of DDX3 were reported with different viruses. On one hand, it was suggested to be involved in the induction of anti-viral mediators [6,262728. On the other hand, HIV and HCV require DDX3 for their replication29303132. In line with the latter, we found DDX3 upregulated upon infection with a maximum expression at 2 d p.i., concordant with recent publications [11, 33] , and viral replication restricted under conditions of DDX3 knockdown . "
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    Full-text · Article · Jun 2015 · PLoS ONE
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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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    Full-text · Article · May 2015 · Cell Reports
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    • "DDX proteins have been implicated in the regulation of gene induction and are involved in other processes, including signal transduction, gene promoter regulation, mRNA splicing, and translational regulation. 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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