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PubMed2004

Structural basis for the control of translation initiation during stress.

During environmental stress, organisms limit protein synthesis by storing inactive ribosomes that are rapidly reactivated when conditions improve. Here we present structural and biochemical data showing that protein Y, an Escherichia coli stress protein, fills the tRNA- and mRNA-binding channel of the small ribosomal subunit to stabilize intact ribosomes. Protein Y inhibits translation initiation during cold shock but not at normal temperatures. Furthermore, protein Y competes with conserved translation initiation factors that, in bacteria, are required for ribosomal subunit dissociation. The mechanism used by protein Y to reduce translation initiation during stress and quickly release ribosomes for renewed translation initiation may therefore occur widely in nature.

Bacterial Proteins↗
PubMed2006

Aerosol delivery of Akt controls protein translation in the lungs of dual luciferase reporter mice.

Lung cancer has emerged as a leading cause of cancer death in the world; however, most of the current conventional therapies are not sufficiently effective in altering the progression of disease. Therefore, development of novel treatment approaches is needed. Although several genes and methods have been used for cancer gene therapy, a number of problems such as specificity, efficacy and toxicity reduce their application. This has led to re-emergence of aerosol gene delivery as a noninvasive method for lung cancer treatment. In this study, nano-sized glucosylated polyethyleneimine (GPEI) was used as a gene delivery carrier to investigate the effects of Akt wild type (WT) and kinase deficient (KD) on Akt-related signaling pathways and protein translation in the lungs of CMV- LucR-cMyc-IRES-LucF dual reporter mice. These mice are a powerful tool for the discrimination between cap-dependent/-independent protein translation. Aerosols containing self-assembled nano-sized GPEI/Akt WT or GPEI/Akt KD were delivered into the lungs of reporter mice through nose-only-inhalation-chamber with the aid of nebulizer. Aerosol delivery of Akt WT caused the increase of protein expression levels of Akt-related signals, whereas aerosol delivery of Akt KD did not. Furthermore, dual luciferase activity assay showed that aerosol delivery of Akt WT enhanced cap-dependent protein translation, whereas a reduction in cap-dependent protein translation by Akt KD was observed. Our results clearly showed that targeting Akt may be a good strategy for prevention as well as treatment of lung cancer. These studies suggest that our aerosol delivery is compatible for in vivo gene delivery which could be used as a noninvasive gene therapy in the future.

Aerosols↗
PubMed2004

Control of translation reinitiation on the cauliflower mosaic virus (CaMV) polycistronic RNA.

Translation of the polycistronic 35S RNA of CaMV (cauliflower mosaic virus) occurs via a reinitiation mechanism, which requires TAV (transactivator/viroplasmin). To allow translation reinitiation of the major open reading frames on the polycistronic RNA, TAV interacts with the host translational machinery via eIF3 (eukaryotic initiation factor 3) and the 60S ribosome. Accumulation of TAV and eIF3 in the polysomal fraction isolated from CaMV-infected cells suggested that TAV prevents loss of eIF3 from the translating ribosomes during the first initiation event. The TAV-eIF3-80S complex could be detected in vitro by sucrose-gradient-sedimentation analysis. The question is whether TAV interacts directly with the 48S preinitiation complex or enters polysomes after the first initiation event. eIF4B, a component of the 48S initiation complex, can preclude formation of the TAV-eIF3 complex via competition with TAV for eIF3 binding; the eIF4B- and TAV-binding sites on eIF3g overlap. eIF4B out-competes TAV for binding to eIF3 and to the eIF3-40S complex. Transient overexpression of eIF4B in plant protoplasts specifically inhibits TAV-mediated transactivation of polycistronic translation. Our results thus indicate that eIF4B precludes TAV-eIF3-40S complex formation during the first initiation event. Consequently, overexpression of TAV in plant protoplasts affects only the second and subsequent initiation events. We propose a model in which TAV enters the host translational machinery at the eIF4B-removal step to stabilize eIF3 within polysomes.

Caulimovirus↗
PubMed1974

Control of translation in cultured cells: continued synthesis and accumulation of messenger RNA in nondividing cultures.

Nontransformed animal fibroblasts in tissue culture regulate total protein and ribosomal RNA synthesis coordinately with changes in the cellular growth state. Here it is shown that the amounts and rates of synthesis of cytoplasmic poly(A)-containing RNA, presumed to be mRNA, do not appreciably change with alterations in growth state. In nongrowing (resting) cultures of BALB/c 3T3 cells presumptive mRNA molecules predominantly accumulate as cytoplasmic ribonucleoprotein particles; the RNA from which can be chased into the polyribosomal structure upon activation of the resting cultures with animal sera. It is suggested that the decreased protein synthetic rate in resting as compared with growing cells is in part due to a failure of preexisting mRNAs to attach to ribosomes and that addition of serum to the tissue culture medium can partially overcome this translational lesion.

Animals↗
PubMed1995

Peptide inhibitors of peptidyltransferase alter the conformation of domains IV and V of large subunit rRNA: a model for nascent peptide control of translation.

Peptides of 5 and 8 residues encoded by the leaders of attenuation regulated chloramphenicol-resistance genes inhibit the peptidyltransferase of microorganisms from the three kingdoms. Therefore, the ribosomal target for the peptides is likely to be a conserved structure and/or sequence. The inhibitor peptides "footprint" to nucleotides of domain V in large subunit rRNA when peptide-ribosome complexes are probed with dimethyl sulfate. Accordingly, rRNA was examined as a candidate for the site of peptide binding. Inhibitor peptides MVKTD and MSTSKNAD were mixed with rRNA phenol-extracted from Escherichia coli ribosomes. The conformation of the RNA was then probed by limited digestion with nucleases that cleave at single-stranded (T1 endonuclease) and double-stranded (V1 endonuclease) sites. Both peptides selectively altered the susceptibility of domains IV and V of 23S rRNA to digestion by T1 endonuclease. Peptide effects on cleavage by V1 nuclease were observed only in domain V. The T1 nuclease susceptibility of domain V of in vitro-transcribed 23S rRNA was also altered by the peptides, demonstrating that peptide binding to the rRNA is independent of ribosomal protein. We propose the peptides MVKTD and MSTSKNAD perturb peptidyltransferase center catalytic activities by altering the conformation of domains IV and V of 23S rRNA. These findings provide a general mechanism through which nascent peptides may cis-regulate the catalytic activities of translating ribosomes.

Amino Acid Sequence↗
PubMed2000

Coordinate control of translation and localization of Vg1 mRNA in Xenopus oocytes.

Vg1, a member of the transforming growth factor-beta family involved in mesoderm induction, is translated subsequent to the localization of its mRNA to the vegetal pole of Xenopus oocytes. Whereas the localization of Vg1 mRNA is known to be directed by the 3' untranslated region (UTR), the basis of its translational regulation is unknown. We show here that the 3' UTR of Vg1 causes translational repression of two different reporter mRNAs in Xenopus oocytes. A 350-nucleotide region of the 3' UTR, which is distinct from the localization element, is necessary and sufficient for mediating translational repression and specifically binds to a 38-kDa polypeptide. The translational repression activity is found throughout the oocyte and at all stages of oogenesis. These results suggest that factors colocalized with Vg1 mRNA at the vegetal pole relieve translational repression to allow expression of Vg1 protein.

3' Untranslated Regions↗
PubMedDate not supplied

Neutralizing innate host defenses to control viral translation in HSV-1 infected cells.

Lytic replication of many viruses activates an innate host response designed to prevent the completion of the viral lifecycle, thus impeding the spread of the infection. One branch of the host's complex reaction functions to incapacitate the cellular translational machinery on which the synthesis of viral polypeptides completely depends. This is achieved through the activation of specific protein kinases that phosphorylate eIF2 on its alpha subunit and inactivate this critical translation initiation factor. However, as continued synthesis of viral proteins is required to assemble the viral progeny necessary to transmit the infection to neighboring cells, viruses have developed a variety of strategies to counter this cellular response. Genetic and biochemical studies with herpes simplex virus type 1 (HSV-1) have revealed that the virus produces at least two discrete products at different times during its replicative program that act to prevent the accumulation of phosphorylated eIF2alpha. The gamma(1)34.5 gene product is expressed first, encoding a regulatory subunit that binds the cellular protein phosphatase 1alpha and regenerates pools of active eIF2 by removing the inhibitory phosphate from the alpha subunit. The second function, encoded by the product of the Us11 gene, specifies a double-stranded RNA-binding protein that prevents activation of PKR, a cellular eIF2alpha kinase. Together, both proteins cooperate to overcome the antiviral response of the host and properly regulate translation in HSV-1-infected cells.

Animals↗
PubMed2003

Cup is an eIF4E binding protein required for both the translational repression of oskar and the recruitment of Barentsz.

In Drosophila oocytes, precise localization of the posterior determinant, Oskar, is required for posterior patterning. This precision is accomplished by a localization-dependent translational control mechanism that ensures translation of only correctly localized oskar transcripts. Although progress has been made in identifying localization factors and translational repressors of oskar, none of the known components of the oskar complex is required for both processes. Here, we report the identification of Cup as a novel component of the oskar RNP complex. cup is required for oskar mRNA localization and is necessary to recruit the plus end-directed microtubule transport factor Barentsz to the complex. Surprisingly, Cup is also required to repress the translation of oskar. Furthermore, eukaryotic initiation factor 4E (eIF4E) is localized within the oocyte in a cup-dependent manner and binds directly to Cup in vitro. Thus, Cup is a translational repressor of oskar that is required to assemble the oskar mRNA localization machinery. We propose that Cup coordinates localization with translation.

Animals↗
PubMed1999

Propagation of a novel cytoplasmic, infectious and deleterious determinant is controlled by translational accuracy in Podospora anserina.

Some mutant strains of the filamentous fungus Podospora anserina spontaneously present a growth impairment, which has been called Crippled Growth (CG). CG is caused by a cytoplasmic and infectious factor, C. C is efficiently transmitted during mitosis but is not transmitted to the progeny after sexual crosses. C is induced by stationary phase and cured by various means, most of which stress the cells. Translational accuracy is shown to tightly regulate the propagation of C during the active growth period, because its propagation in dividing hyphae is restricted to cells that display an increased translational accuracy. However, induction of C in stationary phase proceeds independently from the translational accuracy status of the strain. CG does not seem to be accompanied by mitochondrial DNA modifications, although C activates the action of the Determinant of Senescence, another cytoplasmic and infectious element, which causes a disorganization of the mitochondrial genome. In addition, presence of C drastically modifies the spectrum of the mitochondrial DNA rearrangements in AS6-5 mat- cultures during Senescence. C seems to belong to the growing list of unconventional genetic elements. The biological significance of such elements is discussed.

Ascomycota↗
PubMed1992

Control of translational repression by protein-protein interactions.

The coat protein of the RNA bacteriophage MS2 is a translational repressor and interacts with a specific RNA stem-loop to inhibit translation of the viral replicase gene. As part of an effort to dissect genetically its RNA binding function, mutations were identified in the coat protein sequence that suppress mutational defects in the translational operator. Each of the mutants displayed a super-repressor phenotype, repressing translation from the wild-type and a variety of mutant operators better than did the wild-type coat protein. At least one mutant probably binds RNA more tightly than wild-type. The other mutants, however, were defective for assembly of virus-like particles, and self-associated predominantly as dimers. It is proposed that this assembly defect accounts for their super-repressor characteristics, since failure to assemble into virus-like particles elevates the effective concentration of repressor dimers. This hypothesis is supported by the observation that deletion of thirteen amino acids known to be important for assembly of dimers into capsids also resulted in the same assembly defect and in super-repressor activity. A second class of assembly defects is also described. Deletion of two amino acids from the C-terminus of coat protein resulted in failure to form capsids, most of the coat protein having the apparent molecular weight expected of trimers. This mutant (dl-8) was completely defective for repressor activity, probably because of an inability to form dimers. These results point out the inter-dependence of the structural and regulatory functions of coat protein.

Amino Acid Sequence↗
PubMed1995

Promoter control of translation in Xenopus oocytes.

The HIV-1 promoter directs the high level production of transcripts in Xenopus oocytes. However, despite being exported to the cytoplasm, the transcripts are not translated [M. Braddock, A. M. Thorburn, A. Chambers, G. D. Elliott, G. J. Anderson, A. J. Kingsman and S. M. Kingsman (1990) Cell, 62, 1123-1133]. We have shown previously that this is a function of promoter sequences and is independent of the TAR RNA element that is normally located at the 5' end of all HIV mRNAs. We now show that a three nucleotide substitution at position -340, upstream of the RNA start site, reverses the translation inhibition. This site coincides with a sequence that can bind the haematopoietic transcription factor GATA. The inhibition of translation can also be reversed by treatment with inhibitors of casein kinase II or by injection into the nucleus of antibodies specific for the FRGY2 family of RNP proteins. We suggest that the -340 site influences the quality of the transcription complex such that transcripts are diverted to a nucleus-dependent translation inhibition pathway.

Animals↗
PubMed2004

Conserved RNA secondary structures in Flaviviridae genomes.

Presented here is a comprehensive computational survey of evolutionarily conserved secondary structure motifs in the genomic RNAs of the family Flaviviridae: This virus family consists of the three genera Flavivirus, Pestivirus and Hepacivirus and the group of GB virus C/hepatitis G virus with a currently uncertain taxonomic classification. Based on the control of replication and translation, two subgroups were considered separately: the genus Flavivirus, with its type I cap structure at the 5' untranslated region (UTR) and a highly structured 3' UTR, and the remaining three groups, which exhibit translation control by means of an internal ribosomal entry site (IRES) in the 5' UTR and a much shorter less-structured 3' UTR. The main findings of this survey are strong hints for the possibility of genome cyclization in hepatitis C virus and GB virus C/hepatitis G virus in addition to the flaviviruses; a surprisingly large number of conserved RNA motifs in the coding regions; and a lower level of detailed structural conservation in the IRES and 3' UTR motifs than reported in the literature. An electronic atlas organizes the information on the more than 150 conserved, and therefore putatively functional, RNA secondary structure elements.

3' Untranslated Regions↗