Requirement of the DEAD-Box Protein Ded1p for Messenger RNA Translation

Chuang, Ronald Y.; Weaver, P.; Liu, Zheng

doi:10.1126/science.275.5305.1468

Cited by 308 publications

(288 citation statements)

References 23 publications

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“…This again suggests that RHA is not a general stimulator of translation and that it must associate with a particular mRNA to exert its effect. RHA and other RNA helicases, such as DDX3 and Ded1, complement RNA helicase eIF4A and, if recruited, can enhance translation of the specific mRNAs (Lee and Hurwitz 1992;Chuang et al 1997;Lee et al 2008). The PCE elements were proposed to tether RHA to some viral and cellular mRNAs (Hartman et al 2006), while our results indicate that 59 SL and LARP6 serve this function for collagen mRNAs.…”

Section: Discussioncontrasting

confidence: 44%

A novel role of RNA helicase A in regulation of translation of type I collagen mRNAs

Manojlovic

Stefanovic²

2011

RNA

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Type I collagen is composed of two a1(I) polypeptides and one a2(I) polypeptide and is the most abundant protein in the human body. Expression of type I collagen is primarily controlled at the level of mRNA stability and translation. Coordinated translation of a(I) and a2(I) mRNAs is necessary for efficient folding of the corresponding peptides into the collagen heterotrimer. In the 59 untranslated region (59 UTR), collagen mRNAs have a unique 59 stem-loop structure (59 SL). La ribonucleoprotein domain family member 6 (LARP6) is the protein that binds 59 SL with high affinity and specificity and coordinates their translation. Here we show that RNA helicase A (RHA) is tethered to the 59 SL of collagen mRNAs by interaction with the C-terminal domain of LARP6. In vivo, collagen mRNAs immunoprecipitate with RHA in an LARP6-dependent manner. Knockdown of RHA prevents formation of polysomes on collagen mRNAs and dramatically reduces synthesis of collagen protein, without affecting the level of the mRNAs. A reporter mRNA with collagen 59 SL is translated three times more efficiently in the presence of RHA than the same reporter without the 59 SL, indicating that the 59 SL is the cis-acting element conferring the regulation. During activation of quiescent cells into collagen-producing cells, expression of RHA is highly up-regulated. We postulate that RHA is recruited to the 59 UTR of collagen mRNAs by LARP6 to facilitate their translation. Thus, RHA has been discovered as a critical factor for synthesis of the most abundant protein in the human body.

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Section: Discussioncontrasting

confidence: 44%

A novel role of RNA helicase A in regulation of translation of type I collagen mRNAs

Manojlovic

Stefanovic²

2011

RNA

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“…DDX3 is also involved in HIV RNA translocation [14]. The DDX3 gene is conserved among eukaryotes, and Ded1 is a budding yeast homolog [23]. Ded1 helicase is essential for initiation of host mRNA translation, and human DDX3 can complement the lethality of Ded1-null yeast cells [24,25].…”

Section: Discussionmentioning

confidence: 99%

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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“…To gauge the selectivity of pateamine for eIF4A, we assessed its effects on another DEAD box family member, Ded1p, implicated in translation initiation in yeast (28,29). No stimulatory (or inhibitory) effect on the helicase activity of Ded1p was observed when pateamine was present in helicase assays with Ded1p (Fig.…”

Section: Resultsmentioning

confidence: 99%

Stimulation of mammalian translation initiation factor eIF4A activity by a small molecule inhibitor of eukaryotic translation

Bordeleau

Matthews

Wojnar

et al. 2005

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

211

245

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RNA helicases are the largest group of enzymes in eukaryotic RNA metabolism. The DEXD͞H-box putative RNA helicases form the helicase superfamily II, whose members are defined by seven highly conserved amino acid motifs, making specific targeting of selected members a challenging pharmacological problem. The translation initiation factor eIF4A is the prototypical DEAD-box RNA helicase that works in conjunction with eIF4B and eIF4H and as a subunit of eIF4F to prepare the mRNA template for ribosome binding, possibly by unwinding the secondary structure proximal to the 5 m 7 GpppN cap structure. We report the identification and characterization of a small molecule inhibitor of eukaryotic translation initiation that acts in an unusual manner by stimulating eIF4A-associated activities. Our results suggest that proper control of eIF4A helicase activity is necessary for efficient ribosome binding and demonstrate the feasibility of selectively targeting DEADbox RNA helicases with small molecules.chemical biology ͉ DEAD-box helicase ͉ pateamine T he ribosome recruitment step of translation initiation is ratelimiting and an important regulatory point whereby cellular environmental cues (e.g., amino acid starvation, mitogenic stimulation, and hypoxia) are linked to the process of translation (1). Two distinct pathways exist for recruitment of the ribosome to the mRNA template. One mechanism is cap-dependent and is facilitated by the presence of the 5Ј cap structure (m 7 GpppN, where N is any nucleotide) on the mRNA. It is catalyzed by the eIF4 class of translation initiation factors and involves the recruitment of ribosomes near the 5Ј end of the mRNA template (1). The second mode involves ribosome recruitment in a cap-independent fashion to an internal ribosome entry site (IRES). Initiation factor requirement for internal ribosome binding varies among IRESes, with some not requiring any factors (2).Preparation of the mRNA template for cap-dependent ribosome recruitment is achieved by eIF4F, eIF4A, eIF4B, eIF4H, and ATP hydrolysis (1). The eIF4F complex is comprised of three subunits: (i) eIF4E, which binds the mRNA cap structure in an ATP-independent fashion; (ii) eIF4A, an RNA helicase that exhibits RNA-dependent ATPase activity and ATPstimulated RNA binding activity (3); and (iii) eIF4G, a modular scaffold that mediates mRNA binding of the 43S preinitiation complex through interactions with eIF3. eIF4B, and eIF4H cooperate with eIF4A to make its helicase activity more processive (4, 5). eIF4A exists as a free form (referred to herein as eIF4A f ) and as a subunit of eIF4F (eIF4A c ) and is thought to cycle through the eIF4F complex during initiation (6-8). When localized in the eIF4F complex, eIF4A c is Ϸ20-fold more efficient as an RNA helicase than when found alone (4, 9), leading to the proposal that eIF4A c is the functional helicase for translation initiation (10). The helicase activity of eIF4F (via eIF4A c ) is thought to unwind local secondary structure in the 5Ј UTR of mRNAs to facilitate cap-dependent ribosome...

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Requirement of the DEAD-Box Protein Ded1p for Messenger RNA Translation

Cited by 308 publications

References 23 publications

A novel role of RNA helicase A in regulation of translation of type I collagen mRNAs

A novel role of RNA helicase A in regulation of translation of type I collagen mRNAs

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

Stimulation of mammalian translation initiation factor eIF4A activity by a small molecule inhibitor of eukaryotic translation

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