Manipulation of the host translation initiation complex eIF4F by DNA viruses

2010 ◽  
Vol 38 (6) ◽  
pp. 1511-1516 ◽  
Author(s):  
Derek Walsh
Keyword(s):  
Translation Initiation ◽  
Mammalian Target Of Rapamycin ◽  
Mrna Translation ◽  
Viral Proteins ◽  
Mitogen Activated Protein Kinase ◽  
Scaffolding Protein ◽  
Initiation Factor ◽  
Viral Protein Synthesis ◽  
Dna Viruses ◽  
Translational Machinery

In the absence of their own translational machinery, all viruses must gain access to host cell ribosomes to synthesize viral proteins and replicate. Ribosome recruitment and scanning of capped host mRNAs is facilitated by the multisubunit eIF (eukaryotic initiation factor) 4F, which consists of a cap-binding protein, eIF4E and an RNA helicase, eIF4A, assembled on a large scaffolding protein, eIF4G. Although inactivated by many viruses to inhibit host translation, a growing number of DNA viruses are being found to employ diverse strategies to stimulate eIF4F activity in infected cells and maximize viral protein synthesis. These strategies include stimulation of cellular mTOR (mammalian target of rapamycin) signalling to inactivate 4E-BPs (eIF4E-binding proteins), a family of translational repressors that limit eIF4E availability and eIF4F complex formation, together with modulating the activity of the eIF4E kinase Mnk (mitogen-activated protein kinase signal-integrating kinase) in a variety of manners to regulate both host and viral mRNA translation. In some cases, specific viral proteins that mediate these signalling events have been identified, whereas others have been shown to interact with host translation initiation factors or complexes and modify their activity and/or subcellular localization. The present review outlines current understanding of the role of eIF4F in the life cycle of various DNA viruses and discusses its potential as a therapeutic target to suppress viral infection.

scholarly journals Activation of a GPCR leads to eIF4G phosphorylation at the 5′ cap and to IRES-dependent translation

2014 ◽  
Vol 52 (3) ◽  
pp. 373-382 ◽  
Author(s):  
Kelly León ◽  
Thomas Boulo ◽  
Astrid Musnier ◽  
Julia Morales ◽  
Christophe Gauthier ◽  
...  
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Mrna Translation ◽  
Hek293 Cells ◽  
Initiation Factor ◽  
Entry Site ◽  
Internal Ribosome Entry ◽  
Translational Machinery ◽  
Phosphorylation Event ◽  
Eukaryotic Initiation Factor 4G ◽  
Molecular Bases

The control of mRNA translation has been mainly explored in response to activated tyrosine kinase receptors. In contrast, mechanistic details on the translational machinery are far less available in the case of ligand-bound G protein-coupled receptors (GPCRs). In this study, using the FSH receptor (FSH-R) as a model receptor, we demonstrate that part of the translational regulations occurs by phosphorylation of the translation pre-initiation complex scaffold protein, eukaryotic initiation factor 4G (eIF4G), in HEK293 cells stably expressing the FSH-R. This phosphorylation event occurred when eIF4G was bound to the mRNA 5′ cap, and probably involves mammalian target of rapamycin. This regulation might contribute to cap-dependent translation in response to FSH. The cap-binding protein eIF4E also had its phosphorylation level enhanced upon FSH stimulation. We also show that FSH-induced signaling not only led to cap-dependent translation but also to internal ribosome entry site (IRES)-dependent translation of some mRNA. These data add detailed information on the molecular bases underlying the regulation of selective mRNA translation by a GPCR, and a topological model recapitulating these mechanisms is proposed.

Regulation of protein synthesis by insulin

2006 ◽  
Vol 34 (2) ◽  
pp. 213-216 ◽  
Author(s):  
C.G. Proud
Keyword(s):  
Protein Synthesis ◽  
Translation Initiation ◽  
Ribosomal Proteins ◽  
Glycogen Synthase ◽  
Mammalian Target Of Rapamycin ◽  
Protein Translation ◽  
Initiation Factor ◽  
Translational Machinery ◽  
Phosphoinositide 3 Kinase ◽  
Eef2 Kinase

Insulin rapidly activates protein synthesis by activating components of the translational machinery including eIFs (eukaryotic initiation factors) and eEFs (eukaryotic elongation factors). In the long term, insulin also increases the cellular content of ribosomes to augment the capacity for protein synthesis. The rapid activation of protein synthesis by insulin is mediated primarily through phosphoinositide 3-kinase. This involves the activation of PKB (protein kinase B). In one case, PKB acts to phosphorylate and inactivate glycogen synthase kinase 3, which in turn phosphorylates and inhibits eIF2B. Insulin elicits the dephosphorylation and activation of eIF2B. Since eIF2B is required for recycling of eIF2, a factor required for all cytoplasmic translation initiation events, this will contribute to overall activation of protein synthesis. PKB also phosphorylates the TSC1 (tuberous sclerosis complex 1)–TSC2 complex to relieve its inhibitory action on the mTOR (mammalian target of rapamycin). Inhibition of mTOR by rapamycin markedly impairs insulin-activated protein synthesis. mTOR controls translation initiation and elongation. The cap-binding factor eIF4E can be sequestered in inactive complexes by 4E-BP1 (eIF4E-binding protein 1). Insulin elicits phosphorylation of 4E-BP1 and its release from eIF4E, allowing eIF4E to form initiation factor complexes. Insulin induces dephosphorylation and activation of eEF2 to accelerate elongation. Both effects are blocked by rapamycin. Insulin inactivates eEF2 kinase by increasing its phosphorylation at several mTOR-regulated sites. Insulin also stimulates synthesis of ribosomal proteins by promoting recruitment of their mRNAs into polyribosomes. This is inhibited by rapamycin. Several key questions remain about, for example, the mechanisms by which mTOR controls 4E-BP1 and eEF2 kinase and the control of ribosomal protein translation.

scholarly journals Inhibition of Polysome Assembly Enhances Imatinib Activity against Chronic Myelogenous Leukemia and Overcomes Imatinib Resistance

2008 ◽  
Vol 28 (20) ◽  
pp. 6496-6509 ◽  
Author(s):  
Min Zhang ◽  
Wuxia Fu ◽  
Sharmila Prabhu ◽  
James C. Moore ◽  
Je Ko ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Translation Initiation ◽  
Mrna Translation ◽  
K562 Cells ◽  
Myelogenous Leukemia ◽  
Mitogen Activated Protein Kinase ◽  
Initiation Factor ◽  
Imatinib Resistance ◽  
Multiple Substrates ◽  
Polysomal Mrna

ABSTRACT Dysregulated mRNA translation is implicated in the pathogenesis of many human cancers including chronic myelogenous leukemia (CML). Because our prior work has specifically implicated translation initiation in CML, we tested compounds that could modulate translation initiation and polysomal mRNA assembly. Here, we evaluated the activity of one such compound, CGP57380, against CML cells and explored its mechanisms of action. First, using polysomal mRNA profiles, we found that imatinib and CGP57380 could independently, and cooperatively, impair polysomal mRNA loading. Imatinib and CGP57380 also synergistically inhibited the growth of Ba/F3-Bcr-Abl and K562 cells via impaired cell cycle entry and increased apoptosis. Mechanistically, CGP57380 inhibited efficient polysomal assembly via two processes. First, it enhanced imatinib-mediated inhibition of eukaryotic initiation factor 4F induction, and second, it independently impaired phosphorylation of ribosomal protein S6 on the preinitiation complex. We also identified multiple substrates of the mTOR, Rsk, and Mnk kinases as targets of CGP57380. Finally, we found a novel negative-feedback loop to the mitogen-activated protein kinase/Mnk pathway that is triggered by CGP57380 and demonstrated that an interruption of the loop further increased the activity of the combination against imatinib-sensitive and -resistant CML cells. Together, this work supports the inhibition of translation initiation as a therapeutic strategy for treating cancers fueled by dysregulated translation.

scholarly journals Transglutaminase 2 mediates hypoxia-induced selective mRNA translation via polyamination of 4EBPs

2020 ◽  
Vol 3 (3) ◽  
pp. e201900565
Author(s):  
Sung-Yup Cho ◽  
Seungun Lee ◽  
Jeonghun Yeom ◽  
Hyo-Jun Kim ◽  
Jin-Haeng Lee ◽  
...  
Keyword(s):  
Translation Initiation ◽  
Mammalian Target Of Rapamycin ◽  
Hypoxia Inducible Factor ◽  
Mrna Translation ◽  
Transglutaminase 2 ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Eukaryotic Translation Initiation Factor ◽  
Eukaryotic Translation ◽  
Eukaryotic Translation Initiation

Hypoxia selectively enhances mRNA translation despite suppressed mammalian target of rapamycin complex 1 activity, contributing to gene expression reprogramming that promotes metastasis and survival of cancer cells. Little is known about how this paradoxical control of translation occurs. Here, we report a new pathway that links hypoxia to selective mRNA translation. Transglutaminase 2 (TG2) is a hypoxia-inducible factor 1–inducible enzyme that alters the activity of substrate proteins by polyamination or crosslinking. Under hypoxic conditions, TG2 polyaminated eukaryotic translation initiation factor 4E (eIF4E)-bound eukaryotic translation initiation factor 4E-binding proteins (4EBPs) at conserved glutamine residues. 4EBP1 polyamination enhances binding affinity for Raptor, thereby increasing phosphorylation of 4EBP1 and cap-dependent translation. Proteomic analyses of newly synthesized proteins in hypoxic cells revealed that TG2 activity preferentially enhanced the translation of a subset of mRNA containing G/C-rich 5′UTRs but not upstream ORF or terminal oligopyrimidine motifs. These results indicate that TG2 is a critical regulator in hypoxia-induced selective mRNA translation and provide a promising molecular target for the treatment of cancers.

scholarly journals Norovirus-mediated modification of the translational landscape via virus and host-induced cleavage of translation initiation factors

2016 ◽  
Author(s):  
Edward Emmott ◽  
Frederic Sorgeloos ◽  
Sarah L. Caddy ◽  
Surender Vashist ◽  
Stanislav Sosnovtsev ◽  
...  
Keyword(s):  
Translation Initiation ◽  
Host Response ◽  
Mrna Translation ◽  
Initiation Factor ◽  
Innate Response ◽  
Viral Protease ◽  
Viral Protein Synthesis ◽  
Initiation Factors ◽  
Translation Initiation Factors ◽  
Covalently Linked

SummaryNoroviruses produce viral RNAs lacking a 5’ cap structure and instead use a virus-encoded VPg protein covalently linked to viral RNA to interact with translation initiation factors and drive viral protein synthesis. Norovirus infection results in the induction of the innate response leading to interferon stimulated gene (ISG) transcription. However the translation of the induced ISG mRNAs is suppressed. Using a novel mass spectrometry approach we demonstrate that diminished host mRNA translation correlates with changes to the composition of the eukaryotic initiation factor complex. The suppression of host ISG translation correlates with the activity of the viral protease (NS6) and the activation of cellular caspases leading to the establishment of an apoptotic environment. These results indicate that noroviruses exploit the differences between viral VPg-dependent and cellular cap-dependent translation in order to diminish the host response to infection.

scholarly journals Virus-Mediated Compartmentalization of the Host Translational Machinery

mBio ◽  
2014 ◽  
Vol 5 (5) ◽  
Author(s):  
Emily A. Desmet ◽  
Lynne J. Anguish ◽  
John S. L. Parker
Keyword(s):  
Protein Synthesis ◽  
Translation Initiation ◽  
Rna Binding ◽  
Viral Proteins ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Viral Translation ◽  
Cytoplasmic Inclusions ◽  
Translational Machinery ◽  
Translational Apparatus

ABSTRACTViruses require the host translational apparatus to synthesize viral proteins. Host stress response mechanisms that suppress translation, therefore, represent a significant obstacle that viruses must overcome. Here, we report a strategy whereby the mammalian orthoreoviruses compartmentalize the translational machinery within virus-induced inclusions known as viral factories (VF). VF are the sites of reovirus replication and assembly but were thought not to contain ribosomes. It was assumed viral mRNAs exited the VF to undergo translation by the cellular machinery, and proteins reentered the factory to participate in assembly. Here, we used ribopuromycylation to visualize active translation in infected cells. These studies revealed that active translation occurs within VF and that ribosomal subunits and proteins required for translation initiation, elongation, termination, and recycling localize to the factory. Interestingly, we observed components of the 43S preinitiation complex (PIC) concentrating primarily at factory margins, suggesting a spatial and/or dynamic organization of translation within the VF. Similarly, the viral single-stranded RNA binding protein σNS localized to the factory margins and had a tubulovesicular staining pattern that extended a short distance from the margins of the factories and colocalized with endoplasmic reticulum (ER) markers. Consistent with these colocalization studies, σNS was found to associate with both eukaryotic translation initiation factor 3 subunit A (eIF3A) and the ribosomal subunit pS6R. Together, these findings indicate that σNS functions to recruit 43S PIC machinery to the primary site of viral translation within the viral factory. Pathogen-mediated compartmentalization of the translational apparatus provides a novel mechanism by which viruses might avoid host translational suppression.IMPORTANCEViruses lack biosynthetic capabilities and depend upon the host for protein synthesis. This dependence requires viruses to evolve mechanisms to coerce the host translational machinery into synthesizing viral proteins in the face of ongoing cellular stress responses that suppress global protein synthesis. Reoviruses replicate and assemble within cytoplasmic inclusions called viral factories. However, synthesis of viral proteins was thought to occur in the cytosol. To identify the site(s) of viral translation, we undertook a microscopy-based approach using ribopuromycylation to detect active translation. Here, we report that active translation occurs within viral factories and that translational factors are compartmentalized within factories. Furthermore, we find that the reovirus nonstructural protein σNS associates with 43S preinitiation complexes at the factory margins, suggesting a role for σNS in translation. Together, virus-induced compartmentalization of the host translational machinery represents a strategy for viruses to spatiotemporally couple viral protein synthesis with viral replication and assembly.

IGF-I stimulates protein synthesis in skeletal muscle through multiple signaling pathways during sepsis

2006 ◽  
Vol 290 (2) ◽  
pp. R313-R321 ◽  
Author(s):  
Thomas C. Vary
Keyword(s):  
Protein Synthesis ◽  
Translation Initiation ◽  
Mammalian Target Of Rapamycin ◽  
Mrna Translation ◽  
Initiation Factor ◽  
S6 Kinase ◽  
Ribosomal Protein S6 ◽  
Igf I ◽  
Upstream Kinase ◽  
Multiple Signaling

Chronic septic abscess formation causes an inhibition of protein synthesis in gastrocnemius not observed in rats with a sterile abscess. Inhibition is associated with an impaired mRNA translation initiation that can be ameliorated by elevating IGF-I but not insulin. The present study investigated the ability of IGF-I signaling to stimulate protein synthesis in gastrocnemius by accelerating mRNA translation initiation. Experiments were performed in perfused hindlimb preparations from rats 5 days after induction of a septic abscess. Protein synthesis in gastrocnemius from septic rats was accelerated twofold by the addition of IGF-I (10 nM) to perfusate. IGF-I increased the phosphorylation of translation repressor 4E-binding protein-1 (4E-BP1). Hyperphosphorylation of 4E-BP1 in response to IGF-I resulted in its dissociation from the inactive eukaryotic initiation factor (eIF) 4E·4E-BP1 complex. Assembly of the active eIF4F complex (as assessed by the association eIF4G with eIF4E) was increased twofold by IGF-I in the perfusate. In addition, phosphorylation of eIF4G and ribosomal protein S6 kinase-1 (S6K1) was also enhanced by IGF-I. Activation of mammalian target of rapamycin, an upstream kinase implicated in phosphorylating both 4E-BP1 and S6K1, was also observed. Thus the ability of IGF-I to accelerate protein synthesis during sepsis may be related to a stimulation of signaling to multiple steps in translation initiation with an ensuing increased phosphorylation of eIF4G, eIF4E availability, and S6K1 phosphorylation.

scholarly journals A Novel Mechanism for the Control of Translation Initiation by Amino Acids, Mediated by Phosphorylation of Eukaryotic Initiation Factor 2B

2007 ◽  
Vol 28 (5) ◽  
pp. 1429-1442 ◽  
Author(s):  
Xuemin Wang ◽  
Christopher G. Proud
Keyword(s):  
Amino Acids ◽  
Protein Synthesis ◽  
Amino Acid ◽  
Translation Initiation ◽  
Mammalian Target Of Rapamycin ◽  
Mrna Translation ◽  
Initiation Factor ◽  
Eukaryotic Initiation Factor ◽  
Amino Acid Deprivation ◽  
Signaling Mechanism

ABSTRACT Eukaryotic initiation factor 2B (eIF2B) plays a key role in controlling the initiation of mRNA translation. eIF2B is heteropentamer whose catalytic (ε) subunit promotes GDP/GTP exchange on eIF2. We show here that depriving human cells of amino acids rapidly results in the inhibition of eIF2B, independently of changes in eIF2 phosphorylation. Although amino acid deprivation also inhibits signaling through the mammalian target of rapamycin complex 1 (mTORC1), the inhibition of eIF2B activity by amino acid starvation is independent of mTORC1. Instead, amino acids repress the phosphorylation of a novel site in eIF2Bε. We identify this site as Ser525, located adjacent to the known phosphoregulatory region in eIF2Bε. Mutation of Ser525 to Ala abolishes the regulation of eIF2B and protein synthesis by amino acids. This indicates that phosphorylation of this site is crucial for the control of eIF2B and protein synthesis by amino acids. These findings identify a new way in which amino acids regulate a key step in translation initiation and indicate that this involves a novel amino acid-sensitive signaling mechanism.

scholarly journals CELF1 is an EIF4E binding protein that promotes translation of epithelial-mesenchymal transition effector mRNAs

2019 ◽  
Author(s):  
Arindam Chaudhury ◽  
Rituraj Pal ◽  
Natee Kongchan ◽  
Na Zhao ◽  
Yingmin Zhu ◽  
...  
Keyword(s):  
Translation Initiation ◽  
Mammalian Cells ◽  
Rna Binding ◽  
Epithelial Mesenchymal Transition ◽  
Binding Protein ◽  
Mrna Translation ◽  
Scaffolding Protein ◽  
Initiation Factor ◽  
Eukaryotic Initiation Factor ◽  
Mesenchymal Transition

AbstractMounting evidence is revealing a granularity within gene regulation that occurs at the level of mRNA translation. Within mammalian cells, canonical cap-dependent mRNA translation is dependent upon the interaction between the m7G cap-binding protein eukaryotic initiation factor 4E (eIF4E) and the scaffolding protein eukaryotic initiation factor 4G (eIF4G), the latter of which facilitates pre-translation initiation complex assembly, mRNA circularization, and ultimately ribosomal scanning. In breast epithelial cells, we previously demonstrated that the CELF1 RNA-binding protein promotes the translation of epithelial to mesenchymal transition (EMT) effector mRNAs containing GU-rich elements (GREs) within their 3’ untranslated regions (UTRs). Here we show that within this context, CELF1 directly binds to both the eIF4E cap-binding protein and Poly(A) binding protein (PABP), promoting translation of GRE-containing mRNAs in mesenchymal cells. Disruption of this CELF1/eIF4E interaction inhibits both EMT induction and experimental metastasis. Our findings illustrate a novel way in which non-canonical mechanisms of translation initiation underlie transitional cellular states within the context of development or human disease.

scholarly journals Correction of eIF2-dependent defects in brain protein synthesis, synaptic plasticity, and memory in mouse models of Alzheimer’s disease

2021 ◽  
Vol 14 (668) ◽  
pp. eabc5429
Author(s):  
Mauricio M. Oliveira ◽  
Mychael V. Lourenco ◽  
Francesco Longo ◽  
Nicole P. Kasica ◽  
Wenzhong Yang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Synthesis ◽  
Synaptic Plasticity ◽  
Translation Initiation ◽  
Mrna Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Postmortem Brain Tissue ◽  
Phosphorylated Eif2α

Neuronal protein synthesis is essential for long-term memory consolidation, and its dysregulation is implicated in various neurodegenerative disorders, including Alzheimer’s disease (AD). Cellular stress triggers the activation of protein kinases that converge on the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), which attenuates mRNA translation. This translational inhibition is one aspect of the integrated stress response (ISR). We found that postmortem brain tissue from AD patients showed increased phosphorylation of eIF2α and reduced abundance of eIF2B, another key component of the translation initiation complex. Systemic administration of the small-molecule compound ISRIB (which blocks the ISR downstream of phosphorylated eIF2α) rescued protein synthesis in the hippocampus, measures of synaptic plasticity, and performance on memory-associated behavior tests in wild-type mice cotreated with salubrinal (which inhibits translation by inducing eIF2α phosphorylation) and in both β-amyloid-treated and transgenic AD model mice. Thus, attenuating the ISR downstream of phosphorylated eIF2α may restore hippocampal protein synthesis and delay cognitive decline in AD patients.

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