The role of the DEAD‐box RNA helicase DDX3 in mRNA metabolism

Soto-Rifo, Ricardo; Ohlmann, Théophile

doi:10.1002/wrna.1165

Cited by 112 publications

(106 citation statements)

References 117 publications

(352 reference statements)

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“…In agreement with previous studies, some DDX3X could also be detected in the nucleus (Fig. 5, insets), consistent with its shuttling across the nuclear envelopes (24,25). Upon infection, DDX3X levels were once again unaffected in HeLa and Vero cells but reduced in 143B cells, as reported above.…”

Section: Resultssupporting

confidence: 93%

The ATP-Dependent RNA Helicase DDX3X Modulates Herpes Simplex Virus 1 Gene Expression

Khadivjam

Stegen

Hogue-Racine

et al. 2017

J Virol

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The human protein DDX3X is a DEAD box ATP-dependent RNA helicase that regulates transcription, mRNA maturation, and mRNA export and translation. DDX3X concomitantly modulates the replication of several RNA viruses and promotes innate immunity. We previously showed that herpes simplex virus 1 (HSV-1), a human DNA virus, incorporates DDX3X into its mature particles and that DDX3X is required for optimal HSV-1 infectivity. Here, we show that viral gene expression, replication, and propagation depend on optimal DDX3X protein levels. Surprisingly, DDX3X from incoming viral particles was not required for the early stages of the HSV-1 infection, but, rather, the protein controlled the assembly of new viral particles. This was independent of the previously reported ability of DDX3X to stimulate interferon type I production. Instead, both the lack and overexpression of DDX3X disturbed viral gene transcription and thus subsequent genome replication. This suggests that in addition to its effect on RNA viruses, DDX3X impacts DNA viruses such as HSV-1 by an interferon-independent pathway. IMPORTANCE Viruses interact with a variety of cellular proteins to complete their life cycle. Among them is DDX3X, an RNA helicase that participates in most aspects of RNA biology, including transcription, splicing, nuclear export, and translation. Several RNA viruses and a limited number of DNA viruses are known to manipulate DDX3X for their own benefit. In contrast, DDX3X is also known to promote interferon production to limit viral propagation. Here, we show that DDX3X, which we previously identified in mature HSV-1 virions, stimulates HSV-1 gene expression and, consequently, virion assembly by a process that is independent of its ability to promote the interferon pathway. KEYWORDS DDX3X, helicase, herpes, host-pathogen interaction, DNA virus, RNA virus, interferon, herpes simplex virus, host-pathogen interactions, transcriptional regulation, translational control T he human DDX3 protein is a member of a large family of DEAD box ATP-dependent RNA helicases. In humans, it is encoded by the X (DDX3X) and Y (DDX3Y) chromosomes, albeit the latter is restricted to testes (1). It participates in different stages of cellular gene expression, such as transcription, mRNA maturation, and mRNA export and translation (2). Given these crucial roles in RNA biology, several RNA viruses interact with DDX3X, often with important consequences for viral replication. This includes hepatitis C virus (HCV), norovirus, West Nile virus, and Japanese encephalitis virus (3-7). This is also the case for HIV and hepatitis B virus (HBV), a peculiar DNA virus that relies on an RNA template and reversed transcription to replicate its genome (8,9). Furthermore, DDX3X also contributes to innate immunity against these viruses. For instance, DDX3X stimulates interferon (IFN) type I production by binding IKK (IB kinase epsilon) and TBK1 (tank-binding kinase 1), leading to IRF3 phosphorylation and activation (10,

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Section: Resultssupporting

confidence: 93%

The ATP-Dependent RNA Helicase DDX3X Modulates Herpes Simplex Virus 1 Gene Expression

Khadivjam

Stegen

Hogue-Racine

et al. 2017

J Virol

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“…NS1, NP, and DDX3 exhibit RNA-binding activity (34)(35)(36). Therefore, we were interested in investigating whether DDX3-NS1 and DDX3-NP interactions were mediated by RNA.…”

Section: Ddx3mentioning

confidence: 99%

“…DDX3 belongs to the DEAD box family of proteins and, like all the helicases in the family, contains a core-helicase domain flanked by a highly variable N-terminal region and a C-terminal region (36,40). The core-helicase domain in human DDX3 comprises residues 168 to 582, while the flanking N-and C-terminal regions comprise residues 1 to 167 and 583 to 662, respectively (41).…”

Section: Ddx3mentioning

confidence: 99%

“…Based on sequence alignment with other DEAD box helicases, the core-helicase domain contains the nine conserved motifs involved in ATPase, helicase, and RNA binding activity (42). The N-terminal region contains a conserved leucine-rich nuclear export signal and is critical for CRM1-mediated nuclear export and eIF4E binding (3,23,36), while an SR-rich region in the C terminus is associated in an interaction with the nuclear export receptor NXF1/TAP (43). Therefore, we constructed Flag-tagged plasmids expressing differ- ent truncated DDX3 mutants and examined their ability to interact with NS1 and NP.…”

Section: Ddx3mentioning

confidence: 99%

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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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“…DDX3 modulates several cellular processes, such as cell growth, apoptosis, innate immunity, and viral infection [1] and may function as an oncogene [1,2] . Examination of cancerous cells and clinical samples shows that DDX3 expression is positively correlated with malignancy and the stemness of different types of cancers [3][4][5][6] .…”

mentioning

confidence: 99%

DDX3-mediated translational activation drives β-catenin signaling and cancer cell motility

Chen¹,

Tarn

2015

Can Cell Microenviron

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The DEAD box RNA helicase DDX3 regulates multiple steps in gene expression and also can mediate cell signaling. Dysregulation of DDX3 has been observed in various cancers, and, notably, its mutations are particularly associated with the wingless (Wnt) type of medulloblastoma. DDX3 can promote cell cycle progression, prevent apoptosis, and increase cell migration in some cancerous cells. Detailed mechanisms by which DDX3 modulates cell adhesion and migration and even the epithelial-mesenchymal transition have only just begun to emerge. We recently demonstrated that DDX3 generally modulates cell adhesion and migration properties in various cell lines, essentially via its activity in promoting the translation of Rac1 mRNA. Moreover, our results indicate that DDX3-activated Rac1 translation is required for Wnt-β-catenin signaling and supports the cell adhesion and migration activities of metastatic cancer cells. This DDX3-Rac1-β-catenin pathway suggests a new role for DDX3 in the Wnt type, and perhaps also other types, of medulloblastoma.To cite this article: Hung-Hsi Chen, et al. DDX3-mediated translational activation drives β-catenin signaling and cancer cell motility. Can Cell Microenviron 2014; 1: e392.

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The role of the DEAD‐box RNA helicase DDX3 in mRNA metabolism

Cited by 112 publications

References 117 publications

The ATP-Dependent RNA Helicase DDX3X Modulates Herpes Simplex Virus 1 Gene Expression

The ATP-Dependent RNA Helicase DDX3X Modulates Herpes Simplex Virus 1 Gene Expression

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

DDX3-mediated translational activation drives β-catenin signaling and cancer cell motility

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