Viral targeting of DEAD box protein 3 reveals its role in TBK1/IKKepsilon-mediated IRF activation
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Article: Viral targeting of DEAD box protein 3 reveals its role in TBK1/IKKepsilon-mediated IRF activation
- SourceAvailable from: PubMed Central
[Show abstract] [Hide abstract] ABSTRACT: While it is well established that human cytomegalovirus (HCMV) upregulates many cellular proteins and incorporates several of them into its virion, little is known about the functional relevance of such virus-host interactions. Two cellular proteins, Grb2 and DDX3, gained our interest as they appeared enriched in virion particles and this incorporation depended on the viral tegument protein pp65, suggesting a functional relevance. We therefore tested whether the level of these proteins is altered upon HCMV infection and whether they support viral replication. Immunoblotting analyses of cellular fractions showed increased levels of both proteins in infected cells with a maximum at 2 d p.i. and a reduction of the soluble Grb2 fraction. Knockdown of either gene by transfection of siRNAs reduced viral spread not only of the cell culture adapted HCMV strain TB40/E but also of recent clinical isolates. Apparently, Grb2 and DDX3 are proviral cellular factors that are upregulated in infected cells.
- "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 . "
[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.
- "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: DDX41, a receptor belonging to the DExD family, functions as a DNA sensor in the mammalian cytoplasm and mediates the antiviral response in host cells. Here, the olive flounder DDX41 was found to have 2267-bp long and encodes a putative protein of 614 amino acid residues. The olive flounder DDX41 mRNA was presented in all tested tissues, and was distinctly expressed in fish naturally infected with LCDV. High expression levels were observed in the heart, liver, kidney and stomach. Furthermore, the olive flounder DDX41 mRNA expression increased significantly in adherent (monocyte-like) cells following stimulation with a DNA virus. Reporter assays showed that the transcriptional activity of the IFN-I promoter was enhanced in DDX41-overexpressing HINAE cells treated with C-di-GMP (dinucleotides). Overexpression of DDX41 also induced the antiviral and inflammatory cytokine gene expression through cytoplasmic C-di-GMP treatment. These results suggest that DDX41 functions as a cytosolic DNA sensor that is capable of inducing antiviral activity and inflammatory responses in the olive flounder. Copyright © 2015. Published by Elsevier Ltd.
- "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. "