The DEAD-box helicase DDX3 substitutes for the cap-binding protein eIF4E to promote compartmentalized translation initiation of the HIV-1 genomic RNA

Soto-Rifo, Ricardo; Rubilar, Paulina S.; Ohlmann, Théophile

doi:10.1093/nar/gkt306

Cited by 85 publications

(104 citation statements)

References 66 publications

Supporting

Mentioning

100

Contrasting

Order By: Relevance

“…Here, we investigated the mechanism of inhibition and demonstrated that DDX3 inhibits viral replication at the level of viral transcription. In contrast, HIV and HCV co-opt DDX3, where it enhances viral replication at viral RNA export and/or translation and viral RNA replication, respectively (20)(21)(22)(23). The regulatory role of DDX3 in transcription is not totally unexpected, because DDX3 has been shown to regulate transcription as well as RNA metabolism.…”

Section: Discussionmentioning

confidence: 99%

“…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%

See 1 more Smart Citation

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

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionmentioning

confidence: 99%

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

View full text Add to dashboard Cite

show abstract

“…DDX3X has been implicated in many aspects of RNA processing [33-35], including the positive regulation of translation of transcripts with complex UTR sequences [36-38]. DDX3X has been implicated in binding mRNAs containing the TAR motif (trans-activation response element) of HIV and in facilitating their translation [37].…”

Section: Introductionmentioning

confidence: 99%

Cancer-Associated Mutants of RNA Helicase DDX3X Are Defective in RNA-Stimulated ATP Hydrolysis

Epling

Grace

Lowe

et al. 2015

Journal of Molecular Biology

View full text Add to dashboard Cite

The DEAD-box RNA helicase DDX3X is frequently mutated in pediatric medulloblastoma. We dissect how these mutants affect DDX3X function with structural, biochemical, and genetic experiments. We identify an N-terminal extension (“ATP-binding loop”, ABL) that is critical for the stimulation of ATP hydrolysis by RNA. We present crystal structures that suggest the ABL interacts dynamically with ATP and confirm the interaction occurs in solution by NMR chemical shift perturbation (CSP) and isothermal calorimetry (ITC). DEAD-box helicases require interaction between two conserved RecA-like helicase domains, D1 and D2 for function. We use NMR CSP to show that DDX3X interacts specifically with double-stranded RNA (dsRNA) through its D1 domain, with contact mediated by residues G302 and G325. Mutants of these residues, G302V and G325E, are associated with pediatric medulloblastoma. These mutants are defective in RNA-stimulated ATP hydrolysis. We show that DDX3X complements the growth defect in a ded1 temperature-sensitive strain of S. pombe, but the cancer-associated mutants G302V and G325E do not complement and exhibit protein expression defects. Taken together, our results suggest that impaired translation of important mRNA targets by mutant DDX3X represents a key step in the development of medulloblastoma.

show abstract

“…DDX1, DDX3 and DDX17 promote Rev-dependent HIV-1 RNA export (Fang et al, 2004;Naji et al, 2012;Yedavalli et al, 2004). In addition to its role in HIV-1 RNA export, DDX3 also enhances HIV-1 translation (Geissler et al, 2012;Lai et al, 2010Lai et al, , 2008Soto-Rifo et al, 2012, 2013. Upf1 and DDX17 are involved in HIV-1 RNA degradation (Ajamian et al, 2008;Zhu et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

DDX17 promotes the production of infectious HIV-1 particles through modulating viral RNA packaging and translation frameshift

et al. 2013

View full text Add to dashboard Cite

RNA helicases are a large family of proteins that rearrange RNA structures and remodel ribonucleic protein complexes using energy derived from hydrolysis of nucleotide triphosphates. They have been shown to participate in every step of RNA metabolism. In the past decade, an increasing number of helicases were shown to promote or inhibit the replication of different viruses, including human immunodeficiency virus type 1. Among these helicases, the DEAD-box RNA helicase DDX17 was recently reported to modulate HIV-1 RNA stability and export. In this study, we further show that the helicase activity of DDX17 is required for the production of infectious HIV-1 particles. Over expression of the DDX17 mutant DQAD in HEK293 cells reduces the amount of packaged viral genomic RNA and diminishes HIV-1 Gag-Pol frameshift. Altogether, these data demonstrate that DDX17 promotes the production of HIV-1 infectious particles by modulating HIV-1 RNA metabolism.

show abstract

The DEAD-box helicase DDX3 substitutes for the cap-binding protein eIF4E to promote compartmentalized translation initiation of the HIV-1 genomic RNA

Cited by 85 publications

References 66 publications

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

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

Cancer-Associated Mutants of RNA Helicase DDX3X Are Defective in RNA-Stimulated ATP Hydrolysis

DDX17 promotes the production of infectious HIV-1 particles through modulating viral RNA packaging and translation frameshift

Contact Info

Product

Resources

About