Requirement of DDX3 DEAD Box RNA Helicase for HIV-1 Rev-RRE Export Function

Yedavalli, Venkat R. K.; Neuveut, Christine; Chi, Ya‐Hui; Kleiman, Lawrence; Jeang, Kuan‐Teh

doi:10.1016/j.cell.2004.09.029

Cited by 503 publications

(682 citation statements)

References 60 publications

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“…DDX3 as a component of initial RNA sensor RIG-I and MDA5 are IFN-inducible proteins, only traces of which exist in an early phase (o2 h) in the cytoplasm where viral RNA replicate. Previous reports showed that DDX3 binds RNA of poly rA or duplexed RNA [13,14], and our protein analysis solidified this issue: DDX3 efficiently bound polyI:C and stem-loop RNA of viral origin in a solution (data not shown). DDX3 as well as IPS-1 were expressed even without any stimulation ( Fig.…”

Section: Ddx3 Promotes Ips-1-mediated Ifn-b Promoter Activationsupporting

confidence: 78%

“…Previous reports [13,14] and our RNA-binding analysis also speculated that one of the RNA-capture proteins is DDX3 since DDX3 tightly binds polyI:C and dsRNA in fluid phase. These RNA-capture proteins may have a role in the IPS-1-involving molecular platform in cells with early virus infection when only a trace RIG-I protein is expressed.…”

Section: Discussionsupporting

confidence: 57%

“…This alternative function of DDX3 is accelerated by the HCV core protein, since the core protein withdraws DDX3 from the IFN-b-inducing facility, leading to suppression of IFN-b induction and positive regulation of HCV propagation in infected cells. DDX3 is also involved in HIV RNA translocation [14]. The DDX3 gene is conserved among eukaryotes, and Ded1 is a budding yeast homolog [23].…”

Section: Discussionmentioning

confidence: 99%

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DEAD/H BOX 3 (DDX3) helicase binds the RIG‐I adaptor IPS‐1 to up‐regulate IFN‐β‐inducing potential

et al. 2010

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Retinoic acid-inducible gene-I (RIG-I)-like receptors (RLR) are members of the DEAD box helicases, and recognize viral RNA in the cytoplasm, leading to IFN-b induction through the adaptor IFN-b promoter stimulator-1 (IPS-1) (also known as Cardif, mitochondrial antiviral signaling protein or virus-induced signaling adaptor). Since uninfected cells usually harbor a trace of RIG-I, other RNA-binding proteins may participate in assembling viral RNA into the IPS-1 pathway during the initial response to infection. We searched for proteins coupling with human IPS-1 by yeast two-hybrid and identified another DEAD (Asp-Glu-AlaAsp) box helicase, DDX3 (DEAD/H BOX 3). DDX3 can bind viral RNA to join it in the IPS-1 complex. Unlike RIG-I, DDX3 was constitutively expressed in cells, and some fraction of DDX3 is colocalized with IPS-1 around mitochondria. The 622-662 a.a DDX3 C-terminal region (DDX3-C) directly bound to the IPS-1 CARD-like domain, and the whole DDX3 protein also associated with RLR. By reporter assay, DDX3 helped IPS-1 up-regulate IFN-b promoter activation and knockdown of DDX3 by siRNA resulted in reduced IFN-b induction. This activity was conserved on the DDX3-C fragment. DDX3 only marginally enhanced IFN-b promoter activation induced by transfected TANK-binding kinase 1 (TBK1) or I-kappa-B kinase-e (IKKe). Forced expression of DDX3 augmented virus-mediated IFN-b induction and host cell protection against virus infection. Hence, DDX3 is an antiviral IPS-1 enhancer. IntroductionRetinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) are cytoplasmic RNA helicases [1][2][3], which signal the presence of viral RNA through the adaptor, IFN-b promoter stimulator-1 (IPS-1) (also known as mitochondrial antiviral signaling protein/caspase recruitment domain (CARD) adaptor inducing IFN-b (Cardif)/virus-induced signaling adaptor) to produce . IPS-1 localizes on the outer membrane of the mitochondria via its C-terminus [6]. Its Nterminus consists of a CARD domain, which interacts with the CARD domains of RIG-I and MDA5. Viral RNA resulting from penetration or replication are believed to assemble in the CARDinteracting helicase complex to activate the cytoplasmic IFNinducing pathway. Although non-infected cells usually express minimal amounts of RIG-I/MDA5, the final output of type I IFN is efficiently induced at an early stage of infection to protect host cells from viral spreading.Once IPS-1 is activated, the kinase complex consisting of TANK-homologous proteins and virus-activated kinases induce nuclear translocation of IFN regulatory factor-3 (IRF-3) to activate the IFN promoter [8]. NAK-associated protein 1, TANKbinding kinase 1 (TBK1) and I-kappa-B kinase-e (IKKe) are components of the kinase complex that phosphorylates IRF-3 to induce type I IFN [9,10]. RIG-I recognizes products of various RNA viruses, while MDA5 recognizes products of picornaviruses 940Frontline [1,11]. RIG-I and MDA5 share the helicase domain, which is classified into the DEAD (Asp-Glu-Ala-Asp) box helicase...

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Section: Ddx3 Promotes Ips-1-mediated Ifn-b Promoter Activationsupporting

confidence: 78%

Section: Discussionsupporting

confidence: 57%

Section: Discussionmentioning

confidence: 99%

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DEAD/H BOX 3 (DDX3) helicase binds the RIG‐I adaptor IPS‐1 to up‐regulate IFN‐β‐inducing potential

et al. 2010

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“…As a member of DEAD box RNA helicase family, DDX3 is a nucleo-cytoplasmic shuttling protein and possesses RNA-dependent ATPase/helicase activity (You et al, 1999;Yedavalli et al, 2004). Although the precise biological function of DDX3 remains elusive, it has been reported that DDX3 is involved in many cellular processes.…”

mentioning

confidence: 99%

“…Additionally, owing to its association with functional spliceosomes, DDX3 has been suggested to be involved in RNA splicing (Zhou et al, 2002). Most interestingly, DDX3 is not only required for HIV Rev-RRE export (Yedavalli et al, 2004), but also interacts with hepatitis C virus (HCV) core protein (Mamiya and Worman, 1999;Owsianka and Patel, 1999;You et al, 1999), suggesting a role in the life cycle or pathogenesis of certain viruses. More recently, we demonstrated that DDX3 harbors tumor-growth suppressive ability and can modulate the transcriptional activity of the p21 waf1/cip1 promoter through physical interaction with Sp1 (Chao et al, 2006).…”

mentioning

confidence: 99%

Candidate tumor suppressor DDX3 RNA helicase specifically represses cap-dependent translation by acting as an eIF4E inhibitory protein

Shih¹,

Tsai²,

Chao³

et al. 2007

Oncogene

163

199

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DDX3 is a human RNA helicase with plethoric functions. Our previous studies have indicated that DDX3 is a transcriptional regulator and functions as a tumor suppressor. In this study, we use a bicistronic reporter to demonstrate that DDX3 specifically represses cap-dependent translation but enhances hepatitis C virus internal ribosome entry site-mediated translation in vivo in a helicase activity-independent manner. To elucidate how DDX3 modulates translation, we identified translation initiation factor eukaryotic initiation factor 4E (eIF4E) as a DDX3-binding partner. Interestingly, DDX3 utilizes a consensus eIF4E-binding sequence YIPPHLR to interact with the functionally important dorsal surface of eIF4E in a similar manner to other eIF4E-binding proteins. Furthermore, cap affinity chromatography analysis suggests that DDX3 traps eIF4E in a translationally inactive complex by blocking interaction with eIF4G. Point mutations within the consensus eIF4E-binding motif in DDX3 impair its ability to bind eIF4E and result in a loss of DDX3's regulatory effects on translation. All these features together indicate that DDX3 is a new member of the eIF4E inhibitory proteins involved in translation initiation regulation. Most importantly, this DDX3-mediated translation regulation also confers the tumor suppressor function on DDX3. Altogether, this study demonstrates regulatory roles and action mechanisms for DDX3 in translation, cell growth and likely viral replication.

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DDX3 participates in miRNA biogenesis and RNA interference through translational control of PACT and interaction with AGO2

Lai,

Yu,

Chen

et al. 2024

FEBS Open Bio

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DDX3 is a DEAD‐box RNA helicase that plays multiple roles in RNA metabolism, including translation. We previously reported that DDX3 is required for translation of PACT, a binding partner of Dicer, suggesting a role for DDX3 in microRNA (miRNA) biogenesis and RNA interference (RNAi). Emerging evidence suggests that DDX3 plays a vital role in tumorigenesis and cancer progression, however, its underlying mechanism is still not fully understood. Here, we showed that the control of PACT by DDX3 is conserved in human cells and Caenorhabditis elegans. Using a miRNA microarray, we found that DDX3 regulates the expression of a small subset of cancer‐related miRNAs. These oncogenic miRNAs were down‐regulated by knockdown of DDX3 or PACT and up‐regulated by overexpression of DDX3 or PACT in HEK293T cells. Similar results were obtained in human cancer HCT116 and HeLa cells. Dual luciferase reporter assay showed that DDX3 and PACT are required for short hairpin RNA (shRNA)‐induced RNAi. We also performed co‐immunoprecipitation to confirm the interaction between DDX3 and AGO2, a significant component of the RNA‐induced silencing complex, supporting a role for DDX3 in the RNAi pathway. We further examined the effects of DDX3 and PACT on cell proliferation, and stable overexpression of DDX3 in HEK293 cells results in loss of contact inhibition of cell growth. Hence, we propose that DDX3 may participate in cancer development by regulating the RNAi pathway.

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Requirement of DDX3 DEAD Box RNA Helicase for HIV-1 Rev-RRE Export Function

Cited by 503 publications

References 60 publications

DEAD/H BOX 3 (DDX3) helicase binds the RIG‐I adaptor IPS‐1 to up‐regulate IFN‐β‐inducing potential

DEAD/H BOX 3 (DDX3) helicase binds the RIG‐I adaptor IPS‐1 to up‐regulate IFN‐β‐inducing potential

Candidate tumor suppressor DDX3 RNA helicase specifically represses cap-dependent translation by acting as an eIF4E inhibitory protein

DDX3 participates in miRNA biogenesis and RNA interference through translational control of PACT and interaction with AGO2

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