Cellular DDX3 regulates Japanese encephalitis virus replication by interacting with viral un-translated regions

Li, Chen; Ge, Ling-ling; Li, Pengpeng; Wang, Yue; Dai, Jing; Sun, Ming-Xia; Huang, Li; Shen, Zhiqiang; Hu, Xiaochun; Ishag, Hassan Zackaria Ali; Mao, Xiang

doi:10.1016/j.virol.2013.11.008

Cited by 70 publications

(75 citation statements)

References 78 publications

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“…Cell proteins binding to the genome 3′ NCR and/or to a viral replication complex protein may function to facilitate the initiation of minus strand viral RNA synthesis. A number of different cell proteins have been reported to bind to a 3′ NCR flavivirus probe including La, PTB, PABP, NF-9 FBP1, DDX5, eEF1A, TIAR/TIA-1 (De Nova-Ocampo, Villegas-Sepulveda et al 2002, Polacek, Friebe et al 2009, Chien, Liao et al 2011, Gomila, Martin et al 2011, Li, Ge et al 2013, Albornoz, Carletti et al 2014) but the region of the 3′ NCR to which these proteins bound was not mapped and some of these proteins also bound to additional flavivirus RNA terminal sequences (De Nova-Ocampo, Villegas-Sepulveda et al 2002, Yocupicio-Monroy, Padmanabhan et al 2007, Li, Ge et al 2014) as well as to some of the viral proteins (Li, Ge et al 2013, Li, Ge et al 2014). Additional studies identified cell proteins binding to particular regions within the flavivirus 3′ NCR.…”

Section: Cell Protein Involvement In Unpairing Of the Stem At The mentioning

confidence: 99%

“…Both DDX5 and DDX3 have been reported to bind to both the 3′ NCR and the 5′ NCR and to positively regulate genome translation (Li, Ge et al 2014). Poly(A) binding protein (PABP) binds to an unmapped region of the 3′ NCR located 5′ of the dumbbell RNA structures and facilitates in vitro translation (Polacek, Friebe et al 2009).…”

Section: Cell Protein Involvement In Viral Rna Translationmentioning

confidence: 99%

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Functions of the 3′ and 5′ genome RNA regions of members of the genus Flavivirus

Brinton

Basu

2015

Virus Research

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The positive sense genomes of members of the genus Flavivirus in the family Flaviviridae are ~11 kb nts in length and have a 5′ type I cap but no 3′ poly A. The 5′ and 3′ terminal regions contain short conserved sequences that are proposed to be repeated remnants of an ancient sequence. However, the functions of most of these conserved sequences have not yet been determined. The terminal regions of the genome also contain multiple conserved RNA structures. Functional data for many of these structures has been obtained. Three sets of complementary 3′ and 5′ terminal region sequences, some of which are located in conserved RNA structures, interact to form a panhandle structure that is required for initiation of minus strand RNA synthesis with the 5′ terminal structure functioning as the promoter. How the switch from the terminal RNA structure base pairing to the long distance RNA-RNA interaction is triggered and regulated is not well understood but evidence suggests involvement of a cell protein binding to three sites on the 3′ terminal RNA structures and a cis-acting metastable 3′ RNA element in the 3′ terminal structure. Cell proteins may also be involved in facilitating exponential replication of nascent genomic RNA within replication vesicles at later times of infection cycle. Other conserved RNA structures and/or sequences in the 5′ and 3′ terminal regions have been proposed to regulate genome translation. Additional functions of the 5′ and 3′ terminal sequences have also been reported.

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Section: Cell Protein Involvement In Unpairing Of the Stem At The mentioning

confidence: 99%

Section: Cell Protein Involvement In Viral Rna Translationmentioning

confidence: 99%

Functions of the 3′ and 5′ genome RNA regions of members of the genus Flavivirus

Brinton

Basu

2015

Virus Research

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“…Evidence suggests that DDX3 is a host factor coopted by multiple viruses, including HIV and hepatitis C virus (HCV) (19)(20)(21)(22)(23). One report showed that DDX3 facilitates the Rev/Rev-responsive element (RRE)-mediated nuclear export of HIV genomic RNA (21); others then showed that DDX3 promotes HIV-1 genomic RNA translation (23).…”

Section: Upon Entry Into Host Cells Viruses Encounter Host Factors Tmentioning

confidence: 99%

DDX3 DEAD-Box RNA Helicase Is a Host Factor That Restricts Hepatitis B Virus Replication at the Transcriptional Level

Lee

Windisch

et al. 2014

J Virol

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DDX3 is a member of the DEAD-box RNA helicase family, involved in mRNA metabolism, including transcription, splicing, and translation. We previously identified DDX3 as a hepatitis B virus (HBV) polymerase (Pol) binding protein, and by using a transient transfection, we found that DDX3 inhibits HBV replication at the posttranscriptional level, perhaps following encapsidation. To determine the exact mechanism of the inhibition, we here employed a diverse HBV experimental system. Inconsistently, we found that DDX3-mediated inhibition occurs at the level of transcription. By using tetracycline-inducible HBV-producing cells, we observed that lentivirus-mediated DDX3 expression led to a reduced level of HBV RNAs. Importantly, knockdown of DDX3 by short hairpin RNA resulted in augmentation of HBV RNAs in two distinct HBV replication systems: (i) tetracyclineinducible HBV-producing cells and (ii) constitutive HBV-producing HepG2.2.15 cells. Moreover, DDX3 knockdown in HBVsusceptible HepG2-NTCP cells, where covalently closed circular DNA (cccDNA) serves as the template for viral transcription, resulted in increased HBV RNAs, validating that transcription regulation by DDX3 occurs on a physiological template. Overall, our results demonstrate that DDX3 represents an intrinsic host antiviral factor that restricts HBV transcription. IMPORTANCE Upon entry into host cells, viruses encounter host factors that restrict viral infection. During evolution, viruses have acquired the ability to subvert cellular factors that adversely affect their replication. Such host factors include TRIM5␣ and APOBEC3G, which were discovered in retroviruses. The discovery of host restriction factors provided deeper insight into the innate immune response and viral pathogenesis, leading to better understanding of host-virus interactions. In contrast to the case with retroviruses, little is known about host factors that restrict hepatitis B virus (HBV), a virus distantly related to retroviruses. DDX3DEAD box RNA helicase is best characterized as an RNA helicase involved in RNA metabolism, such as RNA processing and translation. Here, we show that DDX3 inhibits HBV infection at the level of viral transcription. C hronic hepatitis B virus (HBV) infection represents a major public health burden, affecting more than 300 million individuals worldwide, and carries a high risk for developing cirrhosis and hepatocellular carcinoma (HCC) (1). HBV virions contain a small, partially double-stranded circular DNA genome of 3.2 kb in length. Although it is a DNA virus, HBV replicates its DNA genome via reverse transcription. Upon infection, the virion DNA is converted into covalently closed circular DNA (cccDNA), which then serves as the template for viral transcription (2). Among the viral transcripts, only pregenomic RNA (pgRNA), 3.5 kb in length, is selectively packaged into nucleocapsids along with HBV polymerase (Pol). Inside the nucleocapsid, the pgRNA is reverse transcribed by HBV Pol to yield relaxed circular (RC) DNA. These mature RC DNA-containin...

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“…Recent studies have revealed that the cellular ATPase/RNA helicase X-linked DEAD-box polypeptide 3 (DDX3) is an essential host factor for the replication of viruses belonging to different families: CMV (13) (Herpesviridae), HIV-1 (14) (Retroviridae), HCV (15)(16)(17)(18), Japanese Encephalitis virus (19), Dengue virus (DENV) (20), West Nile virus (WNV; Flaviviridae) (21), Vaccinia virus (22-24) (Poxviridae), and Norovirus (25) (Caliciviridae). The exact mechanisms of interaction of this protein with individual pathogens are still poorly understood (26).…”

mentioning

confidence: 99%

Human DDX3 protein is a valuable target to develop broad spectrum antiviral agents

Brai

Fazi

Tintori

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

102

110

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Targeting a host factor essential for the replication of different viruses but not for the cells offers a higher genetic barrier to the development of resistance, may simplify therapy regimens for coinfections, and facilitates management of emerging viral diseases. DEADbox polypeptide 3 (DDX3) is a human host factor required for the replication of several DNA and RNA viruses, including some of the most challenging human pathogens currently circulating, such as HIV-1, Hepatitis C virus, Dengue virus, and West Nile virus. Herein, we showed for the first time, to our knowledge, that the inhibition of DDX3 by a small molecule could be successfully exploited for the development of a broad spectrum antiviral agent. In addition to the multiple antiviral activities, hit compound 16d retained full activity against drug-resistant HIV-1 strains in the absence of cellular toxicity. Pharmacokinetics and toxicity studies in rats confirmed a good safety profile and bioavailability of 16d. Thus, DDX3 is here validated as a valuable therapeutic target.broad spectrum antivirals | DDX3 | host factors | resistance | coinfections

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Cellular DDX3 regulates Japanese encephalitis virus replication by interacting with viral un-translated regions

Cited by 70 publications

References 78 publications

Functions of the 3′ and 5′ genome RNA regions of members of the genus Flavivirus

Functions of the 3′ and 5′ genome RNA regions of members of the genus Flavivirus

DDX3 DEAD-Box RNA Helicase Is a Host Factor That Restricts Hepatitis B Virus Replication at the Transcriptional Level

Human DDX3 protein is a valuable target to develop broad spectrum antiviral agents

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