Eukaryotic initiation factor 5A2 regulates expression of antiviral genes
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE196982 | GEO | 2022/08/01
REPOSITORIES: GEO
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Project description:Eukaryotic initiation factor 5A2 regulates expression of antiviral genes
| PRJNA808115 | ENA
Project description:Translation initiation is a highly regulated process which broadly affects eukaryotic gene expression. Eukaryotic initiation factor 3 (eIF3) is a central player in canonical and alternative pathways for ribosome recruitment. Here we have investigated how direct binding of eIF3 contributes to the large and regulated differences in protein output conferred by different 5′-untranslated regions (5′-UTRs) of cellular mRNAs. Using an unbiased high-throughput approach to determine the affinity of budding yeast eIF3 for native 5′-UTRs from 4,252 genes, we demonstrate that eIF3 binds specifically to a subset of 5′-UTRs that contain a short unstructured binding motif, AMAYAA. eIF3 binding mRNAs have higher ribosome density in growing cells and are preferentially translated under certain stress conditions, supporting the functional relevance of this interaction. Our results reveal a new class of translational enhancer and suggest a mechanism by which changes in core initiation factor activity enact mRNA-specific translation programs.
2022-07-06 | GSE180046 | GEO
Project description:Eukaryotic translation initiation factor 4E (eIF4E) is perhaps best known for its function in the initiation of protein synthesis on capped mRNAs in the cytoplasm. However, recent studies have highlighted that eIF4E has many additional functions, which include the nuclear export of specific mRNAs as well as roles in ageing and the translation of some uncapped viral RNAs. This review aims to update the reader on recent developments, including the potential of eIF4E as a therapeutic target.
| S-EPMC3061223 | biostudies-literature
Project description:Eukaryotic initiation factor (eIF) 4A is a DEAD-box RNA-binding protein that plays a pivotal role in translation initiation. Although mammals have two eIF4A paralogs, eIF4A1 and eIF4A2, their redundancy has been long assumed because of high homology and their functional difference has been poorly understood. Here we show that eIF4A paralogs employ differential translation programs. Ribosome profiling of eIF4A1- and eIF4A2-knockout HEK293T cell lines revealed that translation efficiency changes were divergent across transcriptome and distinct group of mRNAs were regulated by each paralog. Our analysis indicates that eIF4A1 and eIF4A2 facilitate translation of specific mRNAs.
2019-10-26 | GSE126298 | GEO
Project description:Cells infected by influenza virus mount a large-scale antiviral response and most cells ultimately initiate cell-death pathways in an attempt to suppress viral replication. We performed a CRISPR/Cas9-knockout selection designed to identify host factors required for replication following viral entry. We identified a large class of presumptive antiviral factors that unexpectedly act as important pro-viral enhancers during influenza virus infection. One of these, IFIT2, is an interferon-stimulated gene with well-established antiviral activity but limited mechanistic understanding. As opposed to suppressing infection, we show here that IFIT2 is instead repurposed by influenza virus to promote viral gene expression. CLIP‐seq demonstrated that IFIT2 binds directly to viral and cellular mRNAs in AU‐rich regions, with bound cellular transcripts enriched in interferon‐stimulated mRNAs. Polysome and ribosome profiling revealed that IFIT2 prevents ribosome pausing on bound mRNAs. Together, the data link IFIT2 binding to enhanced translational efficiency for viral and cellular mRNAs and ultimately viral replication. Our findings establish a model for the normal function of IFIT2 as a protein that increases translation of cellular mRNAs to support antiviral responses and explain how influenza virus uses this same activity to redirect a classically antiviral protein into a pro-viral effector.
2022-02-03 | GSE196010 | GEO
Project description:Zika virus (ZIKV) is an emerging mosquito-borne flavivirus that causes severe outbreaks in human populations. ZIKV infection leads to the accumulation of small non-coding viral RNAs (known as sfRNAs) that are crucial for evasion of antiviral responses and for viral pathogenesis. However, the mechanistic understanding of how sfRNAs function remains incomplete. Here, we use recombinant ZIKVs and ribosome profiling of infected human cells to show that sfRNAs block translation of antiviral genes. Mechanistically, we demonstrate that specific RNA structures present in sfRNAs trigger PKR activation, which instead of limiting viral replication, enhances viral particle production. Although ZIKV infection induces mRNA expression of antiviral genes, translation efficiency of type I interferon and interferon stimulated genes were significantly downregulated by PKR activation. Our results reveal a novel viral adaptation mechanism mediated by sfRNAs, where ZIKV increases its fitness by repurposing the antiviral role of PKR into a proviral factor.
2024-04-28 | GSE254253 | GEO
Project description:Zika virus (ZIKV) is an emerging mosquito-borne flavivirus that causes severe outbreaks in human populations. ZIKV infection leads to the accumulation of small non-coding viral RNAs (known as sfRNAs) that are crucial for evasion of antiviral responses and for viral pathogenesis. However, the mechanistic understanding of how sfRNAs function remains incomplete. Here, we use recombinant ZIKVs and ribosome profiling of infected human cells to show that sfRNAs block translation of antiviral genes. Mechanistically, we demonstrate that specific RNA structures present in sfRNAs trigger PKR activation, which instead of limiting viral replication, enhances viral particle production. Although ZIKV infection induces mRNA expression of antiviral genes, translation efficiency of type I interferon and interferon stimulated genes were significantly downregulated by PKR activation. Our results reveal a novel viral adaptation mechanism mediated by sfRNAs, where ZIKV increases its fitness by repurposing the antiviral role of PKR into a proviral factor.
2024-04-28 | GSE254252 | GEO
Project description:The yeast eukaryotic initiation factor 4B binds the 40S subunit in translation preinitiation complexes (PICs) and promotes mRNA binding. Here we have compared the effects of disrupting eIF4B RNA- and ribosome-binding domains under ~1400 growth conditions. The RNA-binding RRM was dispensable for stress responses, but ribosome binding stimulated by the NTD promoted growth in response to a number of stressors through changes in translation. In particular, the NTD confers a strong growth advantage in the presence of the denaturing reagent, urea, and a number of osmolytes that require robust cellular integrity for survival. Ribosome profiling of cells with and without the NTD of eIF4B reveals changes in translation of mRNAs containing longer than average and highly structured 5-prime untranslated regions both normally, and in response to urea exposure. Because these changes require 40S binding, our results suggest eIF4B regulates mRNA recruitment as a part of the scanning PIC, rather than by activating isolated mRNPs prior to ribosome binding. This analysis indicates the cellular response to urea in yeast includes a translational component, driven by increased translation of mRNAs encoding proteins associated with the cellular periphery, and highlights the importance of the general translation factor eIF4B in adapting to external conditions.
2020-04-15 | GSE139097 | GEO
Project description:The central feature of standard eukaryotic translation initiation is small ribosome subunit loading at the 5' cap followed by its 5' to 3' scanning for a start codon. The preferred start is an AUG codon in an optimal context. Elaborate cellular machinery exists to ensure the fidelity of start codon selection. Eukaryotic initiation factor 1 (eIF1) plays a central role in this process. Here we show that the translation of eIF1 homologs in eukaryotes from diverse taxa involves initiation from an AUG codon in a poor context. Using human eIF1 as a model, we show that this poor context is necessary for an autoregulatory negative feedback loop in which a high level of eIF1 inhibits its own translation, establishing that variability in the stringency of start codon selection is used for gene regulation in eukaryotes. We show that the stringency of start codon selection (preferential utilization of optimal start sites) is increased to a surprising degree by overexpressing eIF1. The capacity for the cellular level of eIF1 to impact initiation through the variable stringency of initiation codon selection likely has significant consequences for the proteome in eukaryotes.
| S-EPMC2964218 | biostudies-literature
Project description:As the amount of available sequence data increases, it becomes apparent that our understanding of translation initiation is far from comprehensive and that prior conclusions concerning the origin of the process are wrong. Contrary to earlier conclusions, key elements of translation initiation originated at the Universal Ancestor stage, for homologous counterparts exist in all three primary taxa. Herein, we explore the evolutionary relationships among the components of bacterial initiation factor 2 (IF-2) and eukaryotic IF-2 (eIF-2)/eIF-2B, i.e., the initiation factors involved in introducing the initiator tRNA into the translation mechanism and performing the first step in the peptide chain elongation cycle. All Archaea appear to posses a fully functional eIF-2 molecule, but they lack the associated GTP recycling function, eIF-2B (a five-subunit molecule). Yet, the Archaea do posses members of the gene family defined by the (related) eIF-2B subunits alpha, beta, and delta, although these are not specifically related to any of the three eukaryotic subunits. Additional members of this family also occur in some (but by no means all) Bacteria and even in some eukaryotes. The functional significance of the other members of this family is unclear and requires experimental resolution. Similarly, the occurrence of bacterial IF-2-like molecules in all Archaea and in some eukaryotes further complicates the picture of translation initiation. Overall, these data lend further support to the suggestion that the rudiments of translation initiation were present at the Universal Ancestor stage.
| S-EPMC19904 | biostudies-literature