Translational control by 5′-untranslated regions of eukaryotic mRNAs

Hinnebusch, Alan G.; Ivanov, Ivaylo P.; Sonenberg, Nahum

doi:10.1126/science.aad9868

Cited by 835 publications

(869 citation statements)

References 60 publications

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“…5d). Consistent with their known importance in controlling translation 16 , the different 5′ leader sequences showed distinct basal translational activities (Extended Data Fig. 7a) and elf18-mediated translational activity increase was confirmed in 15 of them (Fig.…”

supporting

confidence: 72%

Global translational reprogramming is a fundamental layer of immune regulation in plants

Greene

Yoo

et al. 2017

Nature

187

192

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In the absence of specialized immune cells, the need for plants to reprogram transcription to transition from growth-related activities to defence is well understood1, 2. However, little is known about translational changes that occur during immune induction. Using ribosome footprinting (RF), we performed global translatome profiling on Arabidopsis exposed to the microbe-associated molecular pattern (MAMP) elf18. We found that during this pattern-triggered immunity (PTI), translation was tightly regulated and poorly correlated with transcription. Identification of genes with altered translational efficiency (TE) led to the discovery of novel regulators of this immune response. Further investigation of these genes showed that mRNA sequence features are major determinants of the observed TE changes. In the 5′ leader sequences of transcripts with increased TE, we found a highly enriched mRNA consensus sequence, R-motif, consisting of mostly purines. We showed that R-motif regulates translation in response to PTI induction through interaction with poly(A)-binding proteins. Therefore, this study provides not only strong evidence, but also a molecular mechanism for global translational reprogramming during PTI in plants.

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supporting

confidence: 72%

Global translational reprogramming is a fundamental layer of immune regulation in plants

Greene

Yoo

et al. 2017

Nature

187

192

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“…4C). Genes with AUG uORFs had significantly lower translation efficiencies than genes without uORFs (WRST, adjusted P-value <0.05), which is consistent with their general role as translational repressors (Ingolia et al 2009;Hinnebusch et al 2016). In contrast, genes with NCC-uORFs had significantly higher translation efficiencies than genes without uORFs, (WRST, adjusted P-value <0.05).…”

Section: Comparison Of Aug and Ncc Uorf Functional Characteristicssupporting

confidence: 48%

“…Located within transcript leaders of protein coding genes, uORFs are cis-regulatory elements that affect translation of the downstream main ORF (Somers et al 2013;Wethmar 2014;Hinnebusch et al 2016). uORF regulatory effects can be conceptualized through the scanning model of translation initiation, in which the preinitiation complex binds the 5 ′ end of transcript leaders and scans downstream in search of start codons (Hinnebusch and Lorsch 2012).…”

Section: [Supplemental Materials Is Available For This Article]mentioning

confidence: 99%

Conserved non-AUG uORFs revealed by a novel regression analysis of ribosome profiling data

et al. 2017

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Upstream open reading frames (uORFs), located in transcript leaders (5′ UTRs), are potent cis-acting regulators of translation and mRNA turnover. Recent genome-wide ribosome profiling studies suggest that thousands of uORFs initiate with non-AUG start codons. Although intriguing, these non-AUG uORF predictions have been made without statistical control or validation; thus, the importance of these elements remains to be demonstrated. To address this, we took a comparative genomics approach to study AUG and non-AUG uORFs. We mapped transcription leaders in multiple Saccharomyces yeast species and applied a novel machine learning algorithm (uORF-seqr) to ribosome profiling data to identify statistically significant uORFs. We found that AUG and non-AUG uORFs are both frequently found in Saccharomyces yeasts. Although most non-AUG uORFs are found in only one species, hundreds have either conserved sequence or position within Saccharomyces. uORFs initiating with UUG are particularly common and are shared between species at rates similar to that of AUG uORFs. However, non-AUG uORFs are translated less efficiently than AUG-uORFs and are less subject to removal via alternative transcription initiation under normal growth conditions. These results suggest that a subset of non-AUG uORFs may play important roles in regulating gene expression.

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“…3). The 5′ UTR plays a critical role in protein translation efficiency as it represents the site of binding for the preinitiation complex initiation of protein translation [15,16]. For example, the eukaryotic initiation factor-4A (eIF4A) binding to the 5′ UTR is important in the unwinding initiation of protein translation [17] and the secondary structure of the 5′ UTR plays a critical role in binding of eIF1A to mRNA [18].…”

Section: Discussionmentioning

confidence: 99%

Optimization of mRNA untranslated regions for improved expression of therapeutic mRNA

et al. 2018

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ABSTRACTmRNA based therapies hold great promise for the treatment of genetic diseases. However, this therapeutic approach suffers from multiple challenges including the short half-life of exogenously administered mRNA and subsequent protein production. Modulation of untranslated regions (UTR) represents one approach to enhance both mRNA stability and translation efficiency. The current studies describe and validate screening methods using a diverse set of 5′UTR and 3′UTR combinations for improved expression of the Arginase 1 (ARG1) protein, a potential therapeutic mRNA target. Data revealed a number of critical aspects which need to be considered when developing a screening approach for engineering mRNA improvements. First, plasmid-based screening methods do not correlate with protein expression driven by exogenously expressed mRNA. Second, improved ARG1 protein production was driven by increased translation and not improved mRNA stability. Finally, the 5′ UTR appears to be the key driver in protein expression for exogenously delivered mRNA. From the testing of the combinatorial library, the 5′UTR for complement factor 3 (C3) and cytochrome p4502E1 (CYP2E1) showed the largest and most consistent increase in protein expression relative to a reference UTR. Collectively, these data provide important information for the development and optimization of therapeutic mRNAs.

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Translational control by 5′-untranslated regions of eukaryotic mRNAs

Cited by 835 publications

References 60 publications

Global translational reprogramming is a fundamental layer of immune regulation in plants

Global translational reprogramming is a fundamental layer of immune regulation in plants

Conserved non-AUG uORFs revealed by a novel regression analysis of ribosome profiling data

Optimization of mRNA untranslated regions for improved expression of therapeutic mRNA

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