Influenza virus repurposes the antiviral protein IFIT2 to promote translation of viral mRNAs
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ABSTRACT:
PROVIDER: PRJNA802892 | ENA |
REPOSITORIES: ENA
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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
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Project description:In response to foreign and endogenous double-stranded RNA (dsRNA), protein kinase R (PKR) and ribonuclease L (RNase L) reprogram translation in mammalian cells. PKR inhibits translation initiation through eIF2 phosphorylation, which triggers stress granule (SG) formation and promotes translation of stress responsive mRNAs. The mechanisms of RNase L-driven translation repression, its contribution to SG assembly, and its regulation of dsRNA stress-induced mRNAs are unknown. We demonstrate that RNase L drives translational shut-off in response to dsRNA by promoting widespread turnover of mRNAs. This alters stress granule assembly and reprograms translation by only allowing for the translation of mRNAs resistant to RNase L degradation, including numerous antiviral mRNAs such as IFN- . Individual cells differentially activate dsRNA responses revealing variation that can affect cellular outcomes. This identifies bulk mRNA degradation and the resistance of antiviral mRNAs as the mechanism by which RNaseL reprograms translation in response to dsRNA.
2019-07-10 | GSE124144 | GEO
Project description:Rnase L reprograms translation by widespread mRNA turnover escaped by antiviral mRNAs
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Project description:Upon detection of viral infections, cells activate the expression of type I interferons (IFNs) and pro-inflammatory cytokines to control viral dissemination. As part of their antiviral response, cells also trigger the translational shutoff response which prevents translation of viral mRNAs and cellular mRNAs in a non-selective manner. Intriguingly, mRNAs encoding for antiviral factors bypass this translational shutoff, suggesting the presence of additional regulatory mechanisms enabling expression of the self-defence genes. Here, we identified the dsRNA binding protein ILF3 as an essential host factor required for efficient translation of the central antiviral cytokine, IFNB1, and a subset of interferon-stimulated genes. By combining polysome profiling and next-generation sequencing, ILF3 was also found to be necessary to establish the dsRNA-induced transcriptional and translational programs. We propose a central role for the host factor ILF3 in enhancing expression of the antiviral defence mRNAs in cellular conditions where cap-dependent translation is compromised. In this dataset we use polysome profiling in combination with RNA-seq to investigate the effect of ILF3 on the translation of mRNAs in HeLa cells in homeostasis and the antiviral response.
2019-10-25 | GSE130742 | GEO
Project description:In response to viral pathogens, the host upregulates antiviral genes that suppress translation of viral mRNAs. However, induction of such antiviral responses may not be exclusive to viruses as the pathways lie at the intersection of broad inflammatory networks that can also be induced by bacterial pathogens. Using a model of Gram-negative sepsis, we show that propagation of kidney damage initiated by a bacterial origin ultimately involves antiviral responses that result in host translation shutdown. We determined that activation of the Eif2ak2-Eif2α axis is the key mediator of translation initiation block in late phase sepsis. Reversal of this axis mitigated kidney injury. Furthermore, temporal profiling of the kidney translatome revealed that multiple genes involved in formation of the initiation complex were translationally altered during bacterial sepsis. Collectively, our findings implicate that translation shutdown is indifferent to the specific initiating pathogen and is an important determinant of tissue injury in sepsis.
2018-11-16 | GSE122274 | GEO
Project description:In response to viral pathogens, the host upregulates antiviral genes that suppress translation of viral mRNAs. However, induction of such antiviral responses may not be exclusive to viruses as the pathways lie at the intersection of broad inflammatory networks that can also be induced by bacterial pathogens. Using a model of Gram-negative sepsis, we show that propagation of kidney damage initiated by a bacterial origin ultimately involves antiviral responses that result in host translation shutdown. We determined that activation of the Eif2ak2-Eif2α axis is the key mediator of translation initiation block in late phase sepsis. Reversal of this axis mitigated kidney injury. Furthermore, temporal profiling of the kidney translatome revealed that multiple genes involved in formation of the initiation complex were translationally altered during bacterial sepsis. Collectively, our findings implicate that translation shutdown is indifferent to the specific initiating pathogen and is an important determinant of tissue injury in sepsis.
2018-10-06 | GSE120877 | GEO
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Project description:Nascent peptide chain targeting to the endoplasmic reticulum (ER) membrane is required for correct localization and efficient translation of membrane-bound and secreted proteins. However, little is known about the contribution of RNA-binding proteins (RBPs) to the recognition, localization and translation of ER-localized mRNAs. In this work we used biochemical, transcriptomic and proteomic approaches to delineate the role of human HDLBP. PAR-CLIP analysis revealed that HDLBP directly and specifically interacted with more than 80% of all expressed ER-localized mRNAs. Interestingly, the binding to the coding sequence was most prominent for ER-localized mRNAs, while cytosolic mRNAs showed higher binding in the 3’UTR. HDLBP crosslinked strongly to long CU-rich motifs that resided more frequently in coding sequences of ER-localized but not in cytosolic mRNAs. This indicated that the primary sequence composition determines the basis for HDLBP binding specificity and its multivalent interactions with ER-bound mRNAs. PAR-CLIP analysis also revealed direct interactions of HDLBP with the RNA components of the translational apparatus, while in vivo proximity proteomics detected proteins involved in translation and components of the signal recognition particle (SRP). Functional studies using CRISPR-Cas9 HDLBP knockout cell lines in combination with ribosome profiling, pSILAC, and luciferase assays showed decreased translation efficiency of HDLBP target mRNAs, impaired protein synthesis and secretion in the knockout conditions. Finally, HDLBP absence resulted in decrease of lung tumor formation capacity in vivo. These results highlight a general function for HDLBP in the translation of ER -localized mRNAs via the secretory pathway and discover its relevance for cell profileration and tumor progression.
2022-06-09 | PXD018313 | Pride