General and Target-Specific DExD/H RNA Helicases in Eukaryotic Translation Initiation

Shen, Leo; Pelletier, Jerry

doi:10.3390/ijms21124402

Cited by 48 publications

(44 citation statements)

References 174 publications

(267 reference statements)

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“…The recruitment of several eIF3 components also promoted the translation (Fig. 3d), supporting a previous finding that DHX29 cooperates with eIF3 during translation initiation 29,40 . Since several eIF3 components were also pulled down by 3ʹ-CiTIs (Fig.…”

Section: Trans-acting Factors Are Involved In 3ʹ-citi-mediated Translation Enhancementsupporting

confidence: 89%

“…We further observed a direct interaction of DHX29 with HIF1A mRNAs (Extended data Fig. 9c), consistent with its general function as a subunit of the translation initiation complex 40 . Interestingly, the interaction between DHX29 and HIF1A mRNA was nearly eliminated by the 3ʹ-CiTI deletion under hypoxia, whereas this interaction was only reduced by ~50% during normoxia (Fig.…”

Section: ʹ-Citi and Dhx29 Promote Hif1a Translation In Response To Hypoxia In Vitro And In Vivosupporting

confidence: 82%

“…This study also highlights the importance of DHX29 in 3ʹ-CiTI-mediated translation initiation in response to environmental stress. Several RNA helicases (including DHX29, DHX9 and DDX3) were reported to promote translation 29,40 . In particular, DHX29 has been shown to interact with eIF3 to form an active 43S/DHX29 complex 41 .…”

Section: Discussionmentioning

confidence: 99%

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Unbiased screen of human transcriptome reveals an unexpected role of 3′UTRs in translation initiation

Yang

Fan

et al. 2021

Preprint

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Although most eukaryotic mRNAs require a 5ʹ-cap for translation initiation, some can also be translated through a poorly studied cap-independent pathway. Here we developed a circRNA-based system and unbiasedly identified more than 10,000 sequences in the human transcriptome that contain Cap-independent Translation Initiators (CiTIs). Surprisingly, most of the identified CiTIs are located in 3ʹUTRs, which mainly promote translation initiation in mRNAs bearing highly structured 5ʹUTR. Mechanistically, CiTI recruits several translation initiation factors including eIF3 and DHX29, which in turn unwind 5ʹUTR structures and facilitate ribosome scanning. Functionally, we showed that the translation of HIF1A mRNA, an endogenous DHX29 target, is antagonistically regulated by its 5ʹUTR structure and a new 3ʹ-CiTI in response to hypoxia. Therefore, deletion of 3ʹ-CiTI suppresses cell growth in hypoxia and tumor progression in vivo. Collectively, our study uncovers a new regulatory mode for translation where the 3ʹUTR actively participate in the translation initiation.

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Section: Trans-acting Factors Are Involved In 3ʹ-citi-mediated Translation Enhancementsupporting

confidence: 89%

Section: ʹ-Citi and Dhx29 Promote Hif1a Translation In Response To Hypoxia In Vitro And In Vivosupporting

confidence: 82%

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Unbiased screen of human transcriptome reveals an unexpected role of 3′UTRs in translation initiation

Yang

Fan

et al. 2021

Preprint

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“…Our findings are also in line with those of a recent study, which reported that DDX5 suppresses IFN-I antiviral innate immune response by interacting with PP2A-Cβ to deactivate IRF3 [43]. However, because DDX is a large family of conserved RNA-binding proteins, nearly all DDX family members have been demonstrated to regulate cellular metabolism and maintain immune homeostasis through regulating nucleic acid binding and to modulate nucleic acid interactions and RNA-protein complex remodeling in host cells, such as DDX58, MDA5, DHX58, DDX3X, DDX21, DDX19, DDX39A, and DDX46 [2,13,14,15,16,[44][45][46][47][48][49][50][51]. In fact, DDX5 has been demonstrated to regulate transcription in order to play its roles in tumorigenesis, proliferation, differentiation, and metastasis pathways [30,46].…”

Section: Discussionmentioning

confidence: 99%

The RNA helicase DDX5 promotes viral infection via regulating N6-methyladenosine levels on the DHX58 and NFκB transcripts to dampen antiviral innate immunity

Cai

et al. 2021

PLoS Pathog

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Multi-functional DEAD-box helicase 5 (DDX5), which is important in transcriptional regulation, is hijacked by diverse viruses to facilitate viral replication. However, its regulatory effect in antiviral innate immunity remains unclear. We found that DDX5 interacts with the N6-methyladenosine (m6A) writer METTL3 to regulate methylation of mRNA through affecting the m6A writer METTL3–METTL14 heterodimer complex. Meanwhile, DDX5 promoted the m6A modification and nuclear export of transcripts DHX58, p65, and IKKγ by binding conserved UGCUGCAG element in innate response after viral infection. Stable IKKγ and p65 transcripts underwent YTHDF2-dependent mRNA decay, whereas DHX58 translation was promoted, resulting in inhibited antiviral innate response by DDX5 via blocking the p65 pathway and activating the DHX58-TBK1 pathway after infection with RNA virus. Furthermore, we found that DDX5 suppresses antiviral innate immunity in vivo. Our findings reveal that DDX5 serves as a negative regulator of innate immunity by promoting RNA methylation of antiviral transcripts and consequently facilitating viral propagation.

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“…DDX3X and its orthologs, including Ded1 in Saccharomyces cerevisiae , are members of the DEAD-box family of RNA helicases, which have critical roles in many facets of RNA biology and gene expression (for review, see ( 12 )). While DDX3X/Ded1 has been implicated in a number of processes, it has been best characterized as a translation factor ( 13 , 14 ). Current models of eukaryotic translation initiation propose that translation factors, including the 40S ribosomal subunit, first assemble on the mRNA, and this preinitiation complex (PIC) then scans the mRNA, starting from the 5’ cap, for the start codon ( 15 ).…”

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confidence: 99%

Medulloblastoma-associated mutations in the DEAD-box RNA helicase DDX3X/DED1 cause specific defects in translation

Brown

Vergara

Whelan

et al. 2021

Journal of Biological Chemistry

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Medulloblastoma is the most common pediatric brain cancer, and sequencing studies identified frequent mutations in DDX3X , a DEAD-box RNA helicase primarily implicated in translation. Forty-two different sites were identified, suggesting that the functional effects of the mutations are complex. To investigate how these mutations are affecting DDX3X cellular function, we constructed a full set of equivalent mutant alleles in DED1 , the Saccharomyces cerevisiae ortholog of DDX3X , and characterized their effects in vivo and in vitro . Most of the medulloblastoma-associated mutants in DDX3X/DED1 ( ded1-mam ) showed substantial growth defects, indicating that functional effects are conserved in yeast. Further, while translation was affected in some mutants, translation defects affecting bulk mRNA were neither consistent nor correlated with the growth phenotypes. Likewise, increased formation of stress granules in ded1-mam mutants was common but did not correspond to the severity of the mutants’ growth defects. In contrast, defects in translating mRNAs containing secondary structure in their 5’ untranslated regions (UTRs) were found in almost all ded1-mam mutants and correlated well with growth phenotypes. We thus conclude that these specific translation defects, rather than generalized effects on translation, are responsible for the observed cellular phenotypes and likely contribute to DDX3X -mutant medulloblastoma. Examination of ATPase activity and RNA binding of recombinant mutant proteins also did not reveal a consistent defect, indicating that the translation defects are derived from multiple enzymatic deficiencies. This work suggests that future studies into medulloblastoma pathology should focus on this specific translation defect, while taking into account the wide spectrum of DDX3X mutations.

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General and Target-Specific DExD/H RNA Helicases in Eukaryotic Translation Initiation

Cited by 48 publications

References 174 publications

Unbiased screen of human transcriptome reveals an unexpected role of 3′UTRs in translation initiation

Unbiased screen of human transcriptome reveals an unexpected role of 3′UTRs in translation initiation

The RNA helicase DDX5 promotes viral infection via regulating N6-methyladenosine levels on the DHX58 and NFκB transcripts to dampen antiviral innate immunity

Medulloblastoma-associated mutations in the DEAD-box RNA helicase DDX3X/DED1 cause specific defects in translation

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