scholarly journals The Eukaryotic Translation Initiation Factor 4F Complex Restricts Rotavirus Infection via Regulating the Expression of IRF1 and IRF7

2019 ◽  
Vol 20 (7) ◽  
pp. 1580 ◽  
Author(s):  
Sunrui Chen ◽  
Cui Feng ◽  
Yan Fang ◽  
Xinying Zhou ◽  
Lei Xu ◽  
...  
Keyword(s):  
Translation Initiation ◽  
Translation Initiation Factor ◽  
Negative Regulator ◽  
Initiation Factor ◽  
Loss Of Function ◽  
Rotavirus Infection ◽  
Eukaryotic Translation ◽  
Initiation Factors ◽  
Eif4f Complex ◽  
Translation Initiation Factors

The eIF4F complex is a translation initiation factor that closely regulates translation in response to a multitude of environmental conditions including viral infection. How translation initiation factors regulate rotavirus infection remains poorly understood. In this study, the knockdown of the components of the eIF4F complex using shRNA and CRISPR/Cas9 were performed, respectively. We have demonstrated that loss-of-function of the three components of eIF4F, including eIF4A, eIF4E and eIF4G, remarkably promotes the levels of rotavirus genomic RNA and viral protein VP4. Consistently, knockdown of the negative regulator of eIF4F and programmed cell death protein 4 (PDCD4) inhibits the expression of viral mRNA and the VP4 protein. Mechanically, we confirmed that the silence of the eIF4F complex suppressed the protein level of IRF1 and IRF7 that exert potent antiviral effects against rotavirus infection. Thus, these results demonstrate that the eIF4F complex is an essential host factor restricting rotavirus replication, revealing new targets for the development of new antiviral strategies against rotavirus infection.

scholarly journals Resistance to Plum pox virus Strain C in Arabidopsis thaliana and Chenopodium foetidum Involves Genome-Linked Viral Protein and Other Viral Determinants and Might Depend on Compatibility With Host Translation Initiation Factors

2014 ◽  
Vol 27 (11) ◽  
pp. 1291-1301 ◽  
Author(s):  
María Calvo ◽  
Sandra Martínez-Turiño ◽  
Juan Antonio García
Keyword(s):  
Arabidopsis Thaliana ◽  
Translation Initiation ◽  
Viral Protein ◽  
Molecular Mechanisms ◽  
Viral Infections ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Plum Pox Virus ◽  
Initiation Factors ◽  
Translation Initiation Factors

Research performed on model herbaceous hosts has been useful to unravel the molecular mechanisms that control viral infections. The most common Plum pox virus (PPV) strains are able to infect Nicotiana species as well as Chenopodium and Arabidopsis species. However, isolates belonging to strain C (PPV-C) that have been adapted to Nicotiana spp. are not infectious either in Chenopodium foetidum or in Arabidopsis thaliana. In order to determine the mechanism underlying this interesting host-specific behavior, we have constructed chimerical clones derived from Nicotiana-adapted PPV isolates from the D and C strains, which differ in their capacity to infect A. thaliana and C. foetidum. With this approach, we have identified the nuclear inclusion a protein (VPg+Pro) as the major pathogenicity determinant that conditions resistance in the presence of additional secondary determinants, different for each host. Genome-linked viral protein (VPg) mutations similar to those involved in the breakdown of eIF4E-mediated resistance to other potyviruses allow some PPV chimeras to infect A. thaliana. These results point to defective interactions between a translation initiation factor and the viral VPg as the most probable cause of host-specific incompatibility, in which other viral factors also participate, and suggest that complex interactions between multiple viral proteins and translation initiation factors not only define resistance to potyviruses in particular varieties of susceptible hosts but also contribute to establish nonhost resistance.

scholarly journals RNA-binding protein FXR1 drives cMYC translation by mRNA circularization through eIF4F recruitment in ovarian cancer

2020 ◽  
Author(s):  
Jasmine George ◽  
Yongsheng Li ◽  
Deepak Parashar ◽  
Shirng-Wern Tsaih ◽  
Prachi Gupta ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Translation Initiation ◽  
Rna Binding ◽  
Rna Binding Protein ◽  
Eukaryotic Translation ◽  
Initiation Factors ◽  
Eif4f Complex ◽  
Translation Initiation Factors ◽  
Eukaryotic Translation Initiation ◽  
Eukaryotic Translation Initiation Factors

AbstractBackgroundThe RNA-binding protein FXR1 (fragile X-related protein 1) has been implicated as an important regulator of post-transcriptional changes of mRNAs. However, its role in mRNA circularization and recruitment of eukaryotic translation initiation factors for protein translation remains obscure. Here, we aimed to investigate the molecular mechanisms and potential clinical applications of FXR1 in ovarian cancer growth and progression.MethodsFXR1 copy number variation, mRNA expression, protein levels, and their association with prognosis were determined in clinical datasets. An orthotopic ovarian cancer model and bioluminescence imaging were used for preclinical evaluation of FXR1 in vivo. Reverse phase protein arrays (RPPA) and qPCR arrays were performed to identify FXR1’s key targets and downstream effects. SUnSET and polysome profiling were used to determine the translational effects of FXR1. Immunoprecipitation and immunofluorescence were performed to identify the interaction between FXR1 and cMYC mRNA and eIF4F complex. RNA-immunoprecipitation (RIP), RNA electrophoretic mobility shift assays (REMSA), proximity ligation assays (PLA), and biochemical assays were used to identify the specific site on cMYC mRNA to which FXR1 binds to promote mRNA circularization and translation.ResultsWe found that amplification and copy-gain of FXR1 increased the expression of FXR1 mRNA and FXR1 protein in ovarian cancer patients, and these events associated with poor prognosis. We demonstrated that FXR1 binds to AU-rich elements (ARE) within the 3’ untranslated region (3’UTR) of cMYC. As a consequence, FXR1 binding to cMYC 3’UTR leads to the circularization of mRNA and facilitated the recruitment of eukaryotic translation initiation factors (eIFs) to translation start site for improving protein synthesis.ConclusionWe found that FXR1 upregulates a known oncogene, cMYC, by binding to AU-rich elements within the 3’UTR, leading to the recruitment of the eIF4F complex for cMYC translation. Our findings uncover a novel mechanism of action of FXR1 in tumorigenesis and provides opportunities to use FXR1 and its downstream effectors as biomarkers or therapeutic targets in ovarian and other cancers.

scholarly journals Dynamic cycling of eIF2 through a large eIF2B-containing cytoplasmic body

2005 ◽  
Vol 170 (6) ◽  
pp. 925-934 ◽  
Author(s):  
Susan G. Campbell ◽  
Nathaniel P. Hoyle ◽  
Mark P. Ashe
Keyword(s):  
Translation Initiation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Cytoplasmic Body ◽  
Eukaryotic Translation ◽  
Initiation Factors ◽  
Guanine Nucleotide Exchange ◽  
Cellular Stresses

The eukaryotic translation initiation factor 2B (eIF2B) provides a fundamental controlled point in the pathway of protein synthesis. eIF2B is the heteropentameric guanine nucleotide exchange factor that converts eIF2, from an inactive guanosine diphosphate–bound complex to eIF2-guanosine triphosphate. This reaction is controlled in response to a variety of cellular stresses to allow the rapid reprogramming of cellular gene expression. Here we demonstrate that in contrast to other translation initiation factors, eIF2B and eIF2 colocalize to a specific cytoplasmic locus. The dynamic nature of this locus is revealed through fluorescence recovery after photobleaching analysis. Indeed eIF2 shuttles into these foci whereas eIF2B remains largely resident. Three different strategies to decrease the guanine nucleotide exchange function of eIF2B all inhibit eIF2 shuttling into the foci. These results implicate a defined cytoplasmic center of eIF2B in the exchange of guanine nucleotides on the eIF2 translation initiation factor. A focused core of eIF2B guanine nucleotide exchange might allow either greater activity or control of this elementary conserved step in the translation pathway.

scholarly journals The regulation of the mammalian maternal-to-embryonic transition by eukaryotic translation initiation factor 4E

Development ◽  
2021 ◽  
Author(s):  
Yan Li ◽  
Jianan Tang ◽  
Xu Ji ◽  
Min-Min Hua ◽  
Miao Liu ◽  
...  
Keyword(s):  
Embryo Development ◽  
Translation Initiation ◽  
Translation Initiation Factor ◽  
Negative Regulator ◽  
Initiation Factor ◽  
Cell Stage ◽  
Eukaryotic Translation Initiation Factor ◽  
Eukaryotic Translation ◽  
Successful Transition ◽  
Eukaryotic Translation Initiation

Eukaryotic translation initiation factor 4E (eIF4E) mediates CAP-dependent translation. Genetic and inhibitor studies show its expression was required for the successful transition from maternal to embryonic control of mouse embryo development. eIF4E was in the oocyte and in the cytoplasm soon after fertilization, and at each stage of early development. Functional knockout (Eif4e−/-) by PiggyBac (PB) [Act-RFP] transposition caused peri-implantation embryonic lethality due to the failure of normal epiblast formation. Maternal stores of eIF4E supported development up to the 2-4-cell stage after which new expression occurred from both alleles. Inhibition of the maternally acquired stores of eIF4E (4EGI-1 inhibitor) resulted in a block at the 2-cell stage. eIF4E activity was required for new protein synthesis in the 2-cell embryo and knockout embryos had lower translational activity than wildtype embryos. 4E-BP1 is a hypophosphorylation-dependent negative regulator of eIF4E. mTOR activity was required for 4E-BP1 phosphorylation and inhibiting mTOR retarded embryo development. This study shows that eIF4E activity is regulated at key embryonic transitions in the mammalian embryo and is essential for the successful transition to embryonic control of development.

Expression of Translation Initiation Factors eIF-4E and eIF-2α and a Potential Physiologic Role of Continuous Protein Synthesis in Human Platelets

2001 ◽  
Vol 85 (01) ◽  
pp. 142-151 ◽  
Author(s):  
Anping Han ◽  
Linrong Lu ◽  
German Pihan ◽  
Bruce Woda ◽  
Jane-Jane Chen ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Translation Initiation ◽  
Ribosomal Subunit ◽  
Human Platelets ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Protein Synthesis Inhibitors ◽  
Initiation Factors ◽  
Translation Initiation Factors ◽  
Rate Limiting

SummaryIt is generally believed that platelets do not have a functionally significant protein synthetic machinery. However, our analysis demonstrated that normal bone marrow megakaryocytes express high levels of translation initiation factors eIF-4E and eIF-2α and the expression of these protein synthesis initiation factors is continued in platelets (as determined by immunohistochemistry and Western blot analysis). Both eIF-4E and eIF-2α are key regulators of protein synthesis. The eIF-4E is a rate-limiting part of a multisubunit complex, eIF-4F, that binds to the 5’ cap structure present in virtually all eukaryotic mRNAs, and carries out transfer of mRNAs to ribosomes for translation. Translation initiation factor eIF-2α is also a rate-limiting protein which associates with two other proteins to form an eIF-2 initiation factor complex responsible for the transfer of initiator methionyl-tRNA to the 40S ribosomal subunit. We confirm that expression of eIF-4E and eIF-2α is biologically relevant in that platelets continue protein synthesis, albeit at a 16 times lower rate than WBC (as determined by 35S-labeled amino acid incorporation, SDS-PAGE and scintillation counting). Finally, we determined that protein synthesis inhibitors (puromycin and emetine) attenuate the platelet aggregation response to a combination of ADP and epinephrine, but potentiate the response to collagen. Our data are consistent with the existence of different signal transducing pathways mediating the response to ADP/epinephrine and collagen. We suggest that the ADP/epinephrine response is positively affected by continuously synthesized proteins, while the response to collagen is modulated by continuously produced inhibitory proteins. Taken together, our results suggest that continuous protein synthesis is important for platelet function and its role in platelet physiology and pathophysiology deserves further study.

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