Dynamic Interaction of Stress Granules, DDX3X, and IKK-α Mediates Multiple Functions in Hepatitis C Virus Infection

Pène, Véronique; Li, Qisheng; Sodroski, Catherine; Hsu, Cary; Liang, T. Jake

doi:10.1128/jvi.03197-14

Cited by 60 publications

(85 citation statements)

References 60 publications

(87 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: 79%

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: 79%

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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“…DDX3X also enhances MAVS function and this effect is blocked by HCV core protein (Oshiumi et al, 2010). Interestingly, DDX3X bound to the 3´UTR of HCV relocates to stress granules and lipid droplets and activates IKKα, which exerts an NF-κΒ-independent function and translocates to the nucleus to induce the expression of lipogenic genes (Li et al, 2013a;Pene et al, 2015). Thus, sensing HCV genome in the infected cell by DDX3X initiates transcription of lipogenic genes essential for viral assembly.…”

Section: Role Of Hcv In the Modulation Of The Interferon Responsementioning

confidence: 88%

HCV infection, IFN response and the coding and non-coding host cell genome

Carnero

Fortes

2016

Virus Research

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“…For example, the SG protein DDX3 may be redistributed in several ways in order to participate in replication, assembly or even secretion of HCV. For instance, DDX3‐containing SGs may be used to activate lipid droplet formation and studies have demonstrated that DDX3 is recruited to participate in replication complexes (along with G3BP1) . Like P‐body components, DDX3 suppression has been shown to reduce HCV RNA in vitro, in the same manner as G3BP1, ATX2, HuR1, PABP1 and USP10 .…”

Section: How Hcv Plays With P‐bodies and Sgs Without Getting Burnedmentioning

confidence: 99%

“…For instance, DDX3‐containing SGs may be used to activate lipid droplet formation and studies have demonstrated that DDX3 is recruited to participate in replication complexes (along with G3BP1) . Like P‐body components, DDX3 suppression has been shown to reduce HCV RNA in vitro, in the same manner as G3BP1, ATX2, HuR1, PABP1 and USP10 . In addition, sequestering DDX3 may also serve an additional mechanism for counteracting cell immunity since DDX3 is part of the interferon (IFN) response …”

Section: How Hcv Plays With P‐bodies and Sgs Without Getting Burnedmentioning

confidence: 99%

Hepatitis C virus plays with fire and yet avoids getting burned. A review for clinicians on processing bodies and stress granules

Fernández-Carrillo

Pérez‐Vilaró

Díez

et al. 2017

Liver International

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Over the last few years, many reports have defined several types of RNA cell granules composed of proteins and messenger RNA (mRNA) that regulate gene expression on a post-transcriptional level. Processing bodies (P-bodies) and stress granules (SGs) are among the best-known RNA granules, only detectable when they accumulate into very dynamic cytosolic foci. Recently, a tight association has been found between positive-stranded RNA viruses, including hepatitis C virus (HCV), and these granules.The present article offers a comprehensive review on the complex and paradoxical relationship between HCV, P-bodies and SGs from a translational perspective. Despite the fact that components of P-bodies and SGs have assiduously controlled mRNA expression, either by sequestration or degradation, for thousands of years, HCV has learned how to dangerously exploit certain of them for its own benefit in an endless biological war. Thus, HCV has gained the ability to hack ancient host machineries inherited from prokaryotic times. While P-bodies and SGs are crucial to the HCV cycle, in the interferon-free era we still lack detailed knowledge of the mechanisms involved, processes that may underlie the long-term complications of HCV infection.

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Dynamic Interaction of Stress Granules, DDX3X, and IKK-α Mediates Multiple Functions in Hepatitis C Virus Infection

Abstract: The ubiquitous ATP-dependent RNA helicase DDX3X is involved in many cellular functions, including innate immunity, and is a pivotal host factor for hepatitis C virus (HCV) infection. Recently, we showed that DDX3X specifically recognizes the HCV 3= untranslated region (

Cited by 60 publications

References 60 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

HCV infection, IFN response and the coding and non-coding host cell genome

Hepatitis C virus plays with fire and yet avoids getting burned. A review for clinicians on processing bodies and stress granules

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