Distinct interactions of eIF4A and eIF4E with RNA helicase Ded1 stimulate translation in vivo

Gulay, Suna P.; Gupta, Neha; Lorsch, Jon R.; Hinnebusch, Alan G.

doi:10.7554/elife.58243

Cited by 37 publications

(58 citation statements)

References 37 publications

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“…Shorter, unstructured 5'UTRs enable more efficient translation, and secondary structures like Gquadruplexes and stable hairpins have been shown to robustly repress translation by inhibiting preinitiation complex scanning (Arora et al, 2008;Beaudoin and Perreault, 2010;Davuluri et al, 2000;Endoh and Sugimoto, 2016;Halder et al, 2009;Kozak, 1991;Sample et al, 2019). Further, multiple RNA helicases operate during translation initiation to assist in scanning through long and structured 5'UTRs (Gulay et al, 2020;Parsyan et al, 2011;Popa et al, 2016;Rubio et al, 2014;Sen et al, 2019;Sen et al, 2015;Soto-Rifo et al, 2012;Svitkin et al, 2001;Waldron et al, 2019;Wolfe et al, 2014). Despite the well-characterized repression of protein biogenesis associated with impeding progression of scanning ribosomes, the molecular rationale for this repression remained uncharacterized.…”

Section: Discussionmentioning

confidence: 99%

iRQC, a surveillance pathway for 40S ribosomal quality control during mRNA translation initiation

Garshott

Sundaramoorthy

et al. 2021

Preprint

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Since multiple ribosomes can engage a single mRNA, nonuniform ribosome progression can result in collisions. Ribosome collisions during translation elongation elicit a multifaceted ribosome-associated quality control (RQC) response. Despite advanced mechanistic understanding of translation initiation, a parallel RQC pathway that acts on collided preinitiation complexes has not been described. Here, we show that blocking progression of scanning or elongating ribosomes past the start codon triggers uS3 and uS5 ribosomal ubiquitylation. We demonstrate that conditions that activate the integrated stress response can also induce preinitiation complex collisions. The ubiquitin ligase, RNF10, and the deubiquitylating enzyme, USP10, are the key regulators of uS3 and uS5 ubiquitylation. Prolonged uS3 and uS5 ubiquitylation results in 40S, but not 60S, ribosomal protein degradation in an autophagy-independent manner. This study identifies a distinct arm in the RQC pathway, initiation RQC (iRQC), that acts on pervasive ribosome collisions during translation initiation to modulate translation activity and capacity.

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Section: Discussionmentioning

confidence: 99%

iRQC, a surveillance pathway for 40S ribosomal quality control during mRNA translation initiation

Garshott

Sundaramoorthy

et al. 2021

Preprint

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“…The 3’ UTR is considered important for SRP-dependent targeting of mRNAs [reviewed by (76)]; but the SRP is not known to directly interact with the mRNA, and it may interact through another RNA binding protein (77). Ded1 (and DDX3) could serve this role as it interacts with both 5’ and 3’ components of the mRNA [(13,16) and references therein]. Ded1 remains attached to the mRNA during scanning by the 43S ribosomes, assembly of the 48S ribosomes and eventual formation of the 80S ribosomes at the AUG start codon (Figure 15A).…”

Section: Discussionmentioning

confidence: 99%

“…Thus, the functional activity of Ded1 is conserved throughout eukaryotes. Ded1 is considered a general translation-initiation factor that is important for 43S ribosome scanning to the initiation codon and formation of the 48S complex at the AUG codon [ (14)(15)(16) and references therein]. We have shown that Ded1 is a cap-associated factor that actively shuttles between the nucleus and cytoplasm using both the XpoI/Crm1 and Mex67/TAP nuclear pore complexes (13).…”

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confidence: 99%

The DEAD-box RNA helicase Ded1 from yeast is associated with the signal recognition particle (SRP), and its enzymatic activity is regulated by SRP21

Tanner

Yeter-Alat

Belgareh‐Touzé

et al. 2020

Preprint

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The DEAD-box RNA helicase Ded1 is an essential yeast protein involved in translation initiation. It belongs to the DDX3 subfamily of proteins implicated in developmental and cell-cycle regulation. In vitro, the purified Ded1 protein is an ATP-dependent RNA binding protein and an RNA-dependent ATPase, but it lacks RNA substrate specificity and enzymatic regulation. Here we demonstrate by yeast genetics, in situ localization and in vitro biochemical approaches that Ded1 is associated with, and regulated by, the signal recognition particle (SRP), which is a universally conserved ribonucleoprotein complex required for the co-translational translocation of polypeptides into the endoplasmic reticulum lumen and membrane. Ded1 is physically associated with SRP components in vivo and in vitro. Ded1 is genetically linked with SRP proteins. Finally, the enzymatic activity of Ded1 is inhibited by SRP21 with SCR1 RNA. We propose a model where Ded1 actively participates in the translocation of proteins during translation. Our results open a new comprehension of the cellular role of Ded1 during translation.

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“…Results from both reporter assays and ribosome profiling (Ribo-seq) studies are consistent with this proposal, showing that transcripts vary in their sensitivity to DDX3X/Ded1 depending on the extent of predicted structure in their 5’ UTRs ( 18 , 20 , 21 , 22 ). DDX3X/Ded1 also associates with the eIF4F translation complex, which binds to the mRNA early in PIC assembly, and it appears to have a role in this process, again in an mRNA-specific fashion ( 19 , 23 , 24 , 25 , 26 ).…”

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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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Distinct interactions of eIF4A and eIF4E with RNA helicase Ded1 stimulate translation in vivo

Cited by 37 publications

References 37 publications

iRQC, a surveillance pathway for 40S ribosomal quality control during mRNA translation initiation

iRQC, a surveillance pathway for 40S ribosomal quality control during mRNA translation initiation

The DEAD-box RNA helicase Ded1 from yeast is associated with the signal recognition particle (SRP), and its enzymatic activity is regulated by SRP21

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

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