eIF1 discriminates against suboptimal initiation sites to prevent excessive uORF translation genome-wide

Zhou, Fujun; Zhang, Hongen; Kulkarni, Shardul D.; Lorsch, Jon R.; Hinnebusch, Alan G.

doi:10.1261/rna.073536.119

Cited by 42 publications

(29 citation statements)

References 58 publications

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“…We also observed that the effects of both eIF3 mutations are similar to those observed via ribosome profiling of cells expressing mutations targeting eIF4A, eIF4B, and Ded1 (Sen et al, 2015;Sen et al, 2016;Zhou et al, 2020), all of which are thought to contribute either to initial PIC docking to the mRNA or subsequent scanning. These similarities extend to the observation that mRNAs likely to form stable closed-loop structures are least sensitive to mutations targeting these initiation factors and to both eIF3 mutations, whereas mRNAs less likely to form stable closed-loop structures are more sensitive.…”

Section: Discussionsupporting

confidence: 76%

eIF3 and Its mRNA-Entry-Channel Arm Contribute to the Recruitment of mRNAs With Long 5′-Untranslated Regions

Stanciu

Luo

Funes

et al. 2022

Front. Mol. Biosci.

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Translation initiation in eukaryotes is a multi-step pathway and the most regulated phase of translation. Eukaryotic initiation factor 3 (eIF3) is the largest and most complex of the translation initiation factors, and it contributes to events throughout the initiation pathway. In particular, eIF3 appears to play critical roles in mRNA recruitment. More recently, eIF3 has been implicated in driving the selective translation of specific classes of mRNAs. However, unraveling the mechanism of these diverse contributions—and disentangling the roles of the individual subunits of the eIF3 complex—remains challenging. We employed ribosome profiling of budding yeast cells expressing two distinct mutations targeting the eIF3 complex. These mutations either disrupt the entire complex or subunits positioned near the mRNA-entry channel of the ribosome and which appear to relocate during or in response to mRNA binding and start-codon recognition. Disruption of either the entire eIF3 complex or specific targeting of these subunits affects mRNAs with long 5′-untranslated regions and whose translation is more dependent on eIF4A, eIF4B, and Ded1 but less dependent on eIF4G, eIF4E, and PABP. Disruption of the entire eIF3 complex further affects mRNAs involved in mitochondrial processes and with structured 5′-untranslated regions. Comparison of the suite of mRNAs most sensitive to both mutations with those uniquely sensitive to disruption of the entire complex sheds new light on the specific roles of individual subunits of the eIF3 complex.

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Section: Discussionsupporting

confidence: 76%

eIF3 and Its mRNA-Entry-Channel Arm Contribute to the Recruitment of mRNAs With Long 5′-Untranslated Regions

Stanciu

Luo

Funes

et al. 2022

Front. Mol. Biosci.

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“…For example, complement components can be induced in the central nervous system (CNS) resident neurons, astrocytes, oligodendrocytes, cerebrovascular smooth muscle cells, and microglia during development or induced by injury or aging [reviewed in Tenner (2020) ]. These findings have been confirmed recently by single-cell RNA sequencing ( Zhou et al, 2020 ).…”

Section: Introductionsupporting

confidence: 61%

Therapeutic Targeting of the Complement System: From Rare Diseases to Pandemics

2021

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The complement system was discovered at the end of the 19th century as a heat-labile plasma component that “complemented” the antibodies in killing microbes, hence the name “complement.” Complement is also part of the innate immune system, protecting the host by recognition of pathogen-associated molecular patterns. However, complement is multifunctional far beyond infectious defense. It contributes to organ development, such as sculpting neuron synapses, promoting tissue regeneration and repair, and rapidly engaging and synergizing with a number of processes, including hemostasis leading to thromboinflammation. Complement is a double-edged sword. Although it usually protects the host, it may cause tissue damage when dysregulated or overactivated, such as in the systemic inflammatory reaction seen in trauma and sepsis and severe coronavirus disease 2019 (COVID-19). Damage-associated molecular patterns generated during ischemia-reperfusion injuries (myocardial infarction, stroke, and transplant dysfunction) and in chronic neurologic and rheumatic disease activate complement, thereby increasing damaging inflammation. Despite the long list of diseases with potential for ameliorating complement modulation, only a few rare diseases are approved for clinical treatment targeting complement. Those currently being efficiently treated include paroxysmal nocturnal hemoglobinuria, atypical hemolytic-uremic syndrome, myasthenia gravis, and neuromyelitis optica spectrum disorders. Rare diseases, unfortunately, preclude robust clinical trials. The increasing evidence for complement as a pathogenetic driver in many more common diseases suggests an opportunity for future complement therapy, which, however, requires robust clinical trials; one ongoing example is COVID-19 disease. The current review aims to discuss complement in disease pathogenesis and discuss future pharmacological strategies to treat these diseases with complement-targeted therapies. Significance Statement The complement system is the host’s defense friend by protecting it from invading pathogens, promoting tissue repair, and maintaining homeostasis. Complement is a double-edged sword, since when dysregulated or overactivated it becomes the host’s enemy, leading to tissue damage, organ failure, and, in worst case, death. A number of acute and chronic diseases are candidates for pharmacological treatment to avoid complement-dependent damage, ranging from the well established treatment for rare diseases to possible future treatment of large patient groups like the pandemic coronavirus disease 2019.

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“…We identified all possible upstream ORFs (uORFs) within the 5’UTRs starting with ATG and ending with a STOP codon (available as supplementary material). We focused on canonical uORFs with an AUG start codon, which are expected to be translated more efficiently than those initiating with near-cognate codons (NCCs) [ 63 ] . We then used RibORF [ 29 ] to count the number of Ribo-Seq reads that mapped to the P-site in each uORF sequence.…”

Section: Methodsmentioning

confidence: 99%

Impact of uORFs in mediating regulation of translation in stress conditions

Moro

Hermans²,

Ruiz-Orera

et al. 2021

BMC Mol and Cell Biol

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Background A large fraction of genes contains upstream ORFs (uORFs) in the 5′ untranslated region (5’UTR). The translation of uORFs can inhibit the translation of the main coding sequence, for example by causing premature dissociation of the two ribosomal units or ribosome stalling. However, it is currently unknown if most uORFs are inhibitory or if this activity is restricted to specific cases. Here we interrogate ribosome profiling data from three different stress experiments in yeast to gain novel insights into this question. Results By comparing ribosome occupancies in different conditions and experiments we obtain strong evidence that, in comparison to primary coding sequences (CDS), which undergo translational arrest during stress, the translation of uORFs is mostly unaffected by changes in the environment. As a result, the relative abundance of uORF-encoded peptides increases during stress. In general, the changes in the translational efficiency of regions containing uORFs do not seem to affect downstream translation. The exception are uORFs found in a subset of genes that are significantly up-regulated at the level of translation during stress; these uORFs tend to be translated at lower levels in stress conditions than in optimal growth conditions, facilitating the translation of the CDS during stress. We find new examples of uORF-mediated regulation of translation, including the Gcn4 functional homologue fil1 and ubi4 genes in S. pombe. Conclusion We find evidence that the relative amount of uORF-encoded peptides increases during stress. The increased translation of uORFs is however uncoupled from the general CDS translational repression observed during stress. In a subset of genes that encode proteins that need to be rapidly synthesized upon stress uORFs act as translational switches.

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eIF1 discriminates against suboptimal initiation sites to prevent excessive uORF translation genome-wide

Cited by 42 publications

References 58 publications

eIF3 and Its mRNA-Entry-Channel Arm Contribute to the Recruitment of mRNAs With Long 5′-Untranslated Regions

eIF3 and Its mRNA-Entry-Channel Arm Contribute to the Recruitment of mRNAs With Long 5′-Untranslated Regions

Therapeutic Targeting of the Complement System: From Rare Diseases to Pandemics

Impact of uORFs in mediating regulation of translation in stress conditions

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