RNA helicase DDX3: at the crossroad of viral replication and antiviral immunity

Valiente-Echeverría, Fernando; Hermoso, Marcela A.; Soto-Rifo, Ricardo

doi:10.1002/rmv.1845

Cited by 101 publications

(103 citation statements)

References 115 publications

(211 reference statements)

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“…Deregulation of DDX3X expression and mutations in the helicase core of DDX3X are associated with tumors, including medulloblastoma, T-cell lymphoma, lung, colorectal, breast, oral, liver and prostate cancer (19–25), and DDX3X is a potential therapeutic target for cancer treatment (26). DDX3X is also directly targeted by multiple pathogenic viruses including HIV, HCV, other flaviviridae, poxviridae, and HBV (27). The enzyme has been suggested as candidate for the development of broad spectrum antiviral drugs (28).…”

Section: Introductionmentioning

confidence: 99%

Biochemical Differences and Similarities between the DEAD-Box Helicase Orthologs DDX3X and Ded1p

Sharma

Putnam

Jankowsky

2017

Journal of Molecular Biology

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DDX3X is a conserved DEAD-box RNA helicase involved in translation initiation and other processes of RNA metabolism. Mutations in human DDX3X and deregulation of its expression are linked to tumorigenesis and intellectual disability. The protein is also targeted by diverse viruses. Previous studies demonstrated helicase and NTPase activities for DDX3X, but important biochemical features of the enzyme remain unclear. Here, we systematically characterize enzymatic activities of human DDX3X and compare these to its closely related S. cerevisiae ortholog Ded1p. We show that DDX3X, like Ded1p, exclusively utilizes adenosine triphosphates to unwind helices, oligomerizes to function as efficient RNA helicase, and does not unwind DNA duplexes. The ATPase activity of DDX3X is markedly stimulated by RNA and weaker by DNA, although DNA binds to the enzyme. For RNA unwinding, DDX3X shows a greater preference than Ded1p for substrates with unpaired regions 3′ to the duplex over those with 5′ unpaired regions. DDX3X separates longer RNA duplexes faster than Ded1p and is less potent than Ded1p in facilitating strand annealing. Our results reveal that the biochemical activities of human DDX3X are typical for DEAD-box RNA helicases, but diverge quantitatively from its highly similar S. cerevisiae ortholog Ded1p.

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Section: Introductionmentioning

confidence: 99%

Biochemical Differences and Similarities between the DEAD-Box Helicase Orthologs DDX3X and Ded1p

Sharma

Putnam

Jankowsky

2017

Journal of Molecular Biology

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“…The DEAD-box RNA helicases play multi-functional roles in RNA transcription, pre-mRNA splicing, ribosome biogenesis, RNA transport, translation initiation and RNA decay (Edgcomb et al, 2012;Fuller-Pace, 2013;Ishaq et al, 2009;Valiente-Echeverria et al, 2015;Xu et al, 2010). Recently evidence in the literature suggests that interactions with RNA helicases contribute to the lifecycle of positive sense RNA viruses.…”

Section: Introductionmentioning

confidence: 99%

Venezuelan equine encephalitis virus non-structural protein 3 (nsP3) interacts with RNA helicases DDX1 and DDX3 in infected cells

et al. 2016

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The mosquito-borne New World alphavirus, Venezuelan equine encephalitis virus (VEEV) is a Category B select agent with no approved vaccines or therapies to treat infected humans. Therefore it is imperative to identify novel targets that can be targeted for effective therapeutic intervention. We aimed to identify and validate interactions of VEEV nonstructural protein 3 (nsP3) with host proteins and determine the consequences of these interactions to viral multiplication. We used a HA tagged nsP3 infectious clone (rTC-83-nsP3-HA) to identify and validate two RNA helicases: DDX1 and DDX3 that interacted with VEEV-nsP3. In addition, DDX1 and DDX3 knockdown resulted in a decrease in infectious viral titers. Furthermore, we propose a functional model where the nsP3:DDX3 complex interacts with the host translational machinery and is essential in the viral life cycle. This study will lead to future investigations in understanding the importance of VEEV-nsP3 to viral multiplication and apply the information for the discovery of novel host targets as therapeutic options.

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“…Like most other DEAD box helicases, DDX3 is a multifunctional protein with functions related to RNA metabolism, RNA export, ribosome biogenesis, cellular signaling, apoptosis, and viral infection (2,3). DDX3 is known to enhance antiviral innate immunity by interacting with specific proteins of the type I IFN pathway (4). However, many viruses employ viral proteins, such as vaccinia virus (VACV) K7, hepatitis B virus (HBV) polymerase (Pol), and hepatitis C virus (HCV) core protein, to counteract DDX3 function and in turn use DDX3 to enhance its own replication (5)(6)(7)(8)(9).…”

mentioning

confidence: 99%

“…However, many viruses employ viral proteins, such as vaccinia virus (VACV) K7, hepatitis B virus (HBV) polymerase (Pol), and hepatitis C virus (HCV) core protein, to counteract DDX3 function and in turn use DDX3 to enhance its own replication (5)(6)(7)(8)(9). In contrast to its antiviral function, DDX3 is required for the replication of several viruses, such as human immunodeficiency virus (HIV), West Nile virus (WNV), Japanese encephalitis virus (JEV), HCV, and norovirus (4). Therefore, existing literature portrays DDX3 both as a host factor required for viral replication and as a component of the antiviral innate immune response.…”

mentioning

confidence: 99%

DDX3 Interacts with Influenza A Virus NS1 and NP Proteins and Exerts Antiviral Function through Regulation of Stress Granule Formation

Raman

Liu

Pyo

et al. 2016

J Virol

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DDX3 belongs to the DEAD box RNA helicase family and is a multifunctional protein affecting the life cycle of a variety of viruses. However, its role in influenza virus infection is unknown. In this study, we explored the potential role of DDX3 in influenza virus life cycle and discovered that DDX3 is an antiviral protein. Since many host proteins affect virus life cycle by interacting with certain components of the viral machinery, we first verified whether DDX3 has any viral interaction partners. Immunoprecipitation studies revealed NS1 and NP as direct interaction partners of DDX3. Stress granules (SGs) are known to be antiviral and do form in influenza virus-infected cells expressing defective NS1 protein. Additionally, a recent study showed that DDX3 is an important SG-nucleating factor. We thus explored whether DDX3 plays a role in influenza virus infection through regulation of SGs. Our results showed that SGs were formed in infected cells upon infection with a mutant influenza virus lacking functional NS1 (del NS1) protein, and DDX3 colocalized with NP in SGs. We further determined that the DDX3 helicase domain did not interact with NS1 and NP; however, it was essential for DDX3 localization in virus-induced SGs. Knockdown of DDX3 resulted in impaired SG formation and led to increased virus titers. Taken together, our results identified DDX3 as an antiviral protein with a role in virus-induced SG formation. IMPORTANCEDDX3 is a multifunctional RNA helicase and has been reported to be involved in regulating various virus life cycles. However, its function during influenza A virus infection remains unknown. In this study, we demonstrated that DDX3 is capable of interacting with influenza virus NS1 and NP proteins; DDX3 and NP colocalize in the del NS1 virus-induced SGs. Furthermore, knockdown of DDX3 impaired SG formation and led to a decreased virus titer. Thus, we provided evidence that DDX3 is an antiviral protein during influenza virus infection and its antiviral activity is through regulation of SG formation. Our findings provide knowledge about the function of DDX3 in the influenza virus life cycle and information for future work on manipulating the SG pathway and its components to fight influenza virus infection.

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RNA helicase DDX3: at the crossroad of viral replication and antiviral immunity

Cited by 101 publications

References 115 publications

Biochemical Differences and Similarities between the DEAD-Box Helicase Orthologs DDX3X and Ded1p

Biochemical Differences and Similarities between the DEAD-Box Helicase Orthologs DDX3X and Ded1p

Venezuelan equine encephalitis virus non-structural protein 3 (nsP3) interacts with RNA helicases DDX1 and DDX3 in infected cells

DDX3 Interacts with Influenza A Virus NS1 and NP Proteins and Exerts Antiviral Function through Regulation of Stress Granule Formation

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