Internal Ribosome Entry Site-Mediated Translation in Neuronal Protein Synthesis

2018 ◽  
Author(s):  
Martin Holcik
Keyword(s):  
Protein Synthesis ◽  
Internal Ribosome Entry Site ◽  
Normal Function ◽  
Entry Site ◽  
Alternative Mode ◽  
Internal Ribosome Entry ◽  
Neuronal Protein ◽  
Global Protein Synthesis ◽  
Cellular Mrnas ◽  
Specific Mrnas

While the majority of cellular mRNAs are translated by a cap-dependent mechanism, a subset of mRNAs can use an alternative mode of translation that, instead of cap, relies on discreet RNA elements that help to recruit the ribosome. This mode of translation, termed Internal Ribosome Entry Site (IRES)–dependent translation, is particularly important during conditions of compromised global protein synthesis or for a local, precisely timed translation of specific mRNAs. This latter purpose is of considerable importance in cells of the CNS for their normal function. Recently, the disruption of the IRES-mediated translation has also been linked to pathological processes, suggesting that full understanding and targeting of this peculiar mechanism could be used for therapeutic intervention.

scholarly journals Efficient Translation Initiation Directed by the 900-Nucleotide-Long and GC-Rich 5′ Untranslated Region of the Human Retrotransposon LINE-1 mRNA Is Strictly Cap Dependent Rather than Internal Ribosome Entry Site Mediated

2007 ◽  
Vol 27 (13) ◽  
pp. 4685-4697 ◽  
Author(s):  
Sergey E. Dmitriev ◽  
Dmitri E. Andreev ◽  
Ilya M. Terenin ◽  
Ivan A. Olovnikov ◽  
Vladimir S. Prassolov ◽  
...  
Keyword(s):  
Translation Initiation ◽  
Internal Ribosome Entry Site ◽  
Untranslated Region ◽  
High Efficiency ◽  
Rna Binding ◽  
Cultured Cells ◽  
Entry Site ◽  
Internal Ribosome Entry ◽  
Cellular Mrnas ◽  
Internal Initiation

ABSTRACT Retrotransposon L1 is a mobile genetic element of the LINE family that is extremely widespread in the mammalian genome. It encodes a dicistronic mRNA, which is exceptionally rare among eukaryotic cellular mRNAs. The extremely long and GC-rich L1 5′ untranslated region (5′UTR) directs synthesis of numerous copies of RNA-binding protein ORF1p per mRNA. One could suggest that the 5′UTR of L1 mRNA contained a powerful internal ribosome entry site (IRES) element. Using transfection of cultured cells with the polyadenylated monocistronic (L1 5′UTR-Fluc) or bicistronic (Rluc-L1 5′UTR-Fluc) RNA constructs, capped or uncapped, it has been firmly established that the 5′UTR of L1 does not contain an IRES. Uncapping reduces the initiation activity of the L1 5′UTR to that of background. Moreover, the translation is inhibited by upstream AUG codons in the 5′UTR. Nevertheless, this cap-dependent initiation activity of the L1 5′UTR was unexpectedly high and resembles that of the beta-actin 5′UTR (84 nucleotides long). Strikingly, the deletion of up to 80% of the nucleotide sequence of the L1 5′UTR, with most of its stem loops, does not significantly change its translation initiation efficiency. These data can modify current ideas on mechanisms used by 40S ribosomal subunits to cope with complex 5′UTRs and call into question the conception that every long GC-rich 5′UTR working with a high efficiency has to contain an IRES. Our data also demonstrate that the ORF2 translation initiation is not directed by internal initiation, either. It is very inefficient and presumably based on a reinitiation event.

scholarly journals The hnRNA-Binding Proteins hnRNP L and PTB Are Required for Efficient Translation of the Cat-1 Arginine/Lysine Transporter mRNA during Amino Acid Starvation

2009 ◽  
Vol 29 (10) ◽  
pp. 2899-2912 ◽  
Author(s):  
Mithu Majumder ◽  
Ibrahim Yaman ◽  
Francesca Gaccioli ◽  
Vladimir V. Zeenko ◽  
Chuanping Wang ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Amino Acid ◽  
Binding Protein ◽  
Mrna Translation ◽  
Amino Acid Starvation ◽  
Entry Site ◽  
Internal Ribosome Entry ◽  
Polypyrimidine Tract Binding Protein ◽  
Global Protein Synthesis

ABSTRACT The response to amino acid starvation involves the global decrease of protein synthesis and an increase in the translation of some mRNAs that contain an internal ribosome entry site (IRES). It was previously shown that translation of the mRNA for the arginine/lysine amino acid transporter Cat-1 increases during amino acid starvation via a mechanism that utilizes an IRES in the 5′ untranslated region of the Cat-1 mRNA. It is shown here that polypyrimidine tract binding protein (PTB) and an hnRNA binding protein, heterogeneous nuclear ribonucleoprotein L (hnRNP L), promote the efficient translation of Cat-1 mRNA during amino acid starvation. Association of both proteins with Cat-1 mRNA increased during starvation with kinetics that paralleled that of IRES activation, although the levels and subcellular distribution of the proteins were unchanged. The sequence CUUUCU within the Cat-1 IRES was important for PTB binding and for the induction of translation during amino acid starvation. Binding of hnRNP L to the IRES or the Cat-1 mRNA in vivo was independent of PTB binding but was not sufficient to increase IRES activity or Cat-1 mRNA translation during amino acid starvation. In contrast, binding of PTB to the Cat-1 mRNA in vivo required hnRNP L. A wider role of hnRNP L in mRNA translation was suggested by the decrease of global protein synthesis in cells with reduced hnRNP L levels. It is proposed that PTB and hnRNP L are positive regulators of Cat-1 mRNA translation via the IRES under stress conditions that cause a global decrease of protein synthesis.

scholarly journals Vasohibin1, a new IRES trans-acting factor for induction of (lymph)angiogenic factors in early hypoxia

2018 ◽  
Author(s):  
Fransky Hantelys ◽  
Anne-Claire Godet ◽  
Florian David ◽  
Florence Tatin ◽  
Edith Renaud-Gabardos ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Synthesis ◽  
Growth Factors ◽  
Ischemic Heart ◽  
Transcriptional Level ◽  
Angiogenic Growth Factors ◽  
Internal Ribosome Entry ◽  
Global Protein Synthesis ◽  
Specific Mrnas ◽  
Angiogenic Genes

ABSTRACTHypoxia, a major inducer of angiogenesis, is known to trigger major changes of gene expression at the transcriptional level. Furthermore, global protein synthesis is blocked while internal ribosome entry sites (IRES) allow specific mRNAs to be translated. Here we report the transcriptome and translatome signatures of (lymph)angiogenic genes in hypoxic HL-1 cardiomyocytes: most genes are not induced at the transcriptome-, but at the translatome level, including all IRES-containing mRNAs. Our data reveal activation of (lymph)angiogenic mRNA IRESs in early hypoxia. We identify vasohibin1 (VASH1) as an IRES trans-acting factor (ITAF) able to activate FGF1 and VEGFD IRESs in hypoxia while it inhibits several IRESs in normoxia. Thus this new ITAF may have opposite effects on IRES activities. These data suggest a generalized process of IRES-dependent translational induction of (lymph)angiogenic growth factors expression in early hypoxia, whose pathophysiological relevance is to trigger formation of new functional vessels in ischemic heart. VASH1 is not always required, indicating that the IRESome composition is variable, thus allowing subgroups of IRESs to be activated under the control of different ITAFs.

Contribution of internal initiation to translation of cellular mRNAs containing IRESs

2008 ◽  
Vol 36 (4) ◽  
pp. 694-697 ◽  
Author(s):  
Eugenia S. Mardanova ◽  
Ludmila A. Zamchuk ◽  
Nikolai V. Ravin
Keyword(s):  
Internal Ribosome Entry Site ◽  
Entry Site ◽  
Internal Ribosome Entry ◽  
Initiation Of Translation ◽  
Cellular Mrnas ◽  
Dependent Protein ◽  
Low Efficiency ◽  
Internal Initiation ◽  
Cellular Stresses ◽  
Different Tissues

A broad range of cellular stresses lead to the inhibition of translation. Despite this, some cellular mRNAs are selectively translated under these conditions. It is widely supposed that cap-independent internal initiation may maintain efficient translation of particular cellular mRNAs under a variety of stresses and other special conditions when cap-dependent protein synthesis is impaired. However, in spite of a large number of reports focused on the investigation of the regulation of IRES (internal ribosome entry site) activity in different tissues and under various stresses, only rarely is the real efficiency of IRES-driven translation in comparison with cap-dependent translation evaluated. When precisely measured, the efficiencies of candidate IRESs in most cases appeared to be very low and not sufficient to compensate for the reduction of cap-dependent initiation under stresses. The usually low efficiency of internal initiation of translation is inconsistent with postulated biological roles of IRESs.

scholarly journals Alternative Mechanisms to Initiate Translation in Eukaryotic mRNAs

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Encarnación Martínez-Salas ◽  
David Piñeiro ◽  
Noemí Fernández
Keyword(s):  
Translation Initiation ◽  
Internal Ribosome Entry Site ◽  
Entry Site ◽  
Internal Ribosome Entry ◽  
Initiation Of Translation ◽  
Multiple Processes ◽  
Cellular Mrnas ◽  
Eukaryotic Mrnas ◽  
Internal Initiation ◽  
Eukaryotic Organisms

The composition of the cellular proteome is under the control of multiple processes, one of the most important being translation initiation. The majority of eukaryotic cellular mRNAs initiates translation by the cap-dependent or scanning mode of translation initiation, a mechanism that depends on the recognition of the m7G(5′)ppp(5′)N, known as the cap. However, mRNAs encoding proteins required for cell survival under stress bypass conditions inhibitory to cap-dependent translation; these mRNAs often harbor internal ribosome entry site (IRES) elements in their 5′UTRs that mediate internal initiation of translation. This mechanism is also exploited by mRNAs expressed from the genome of viruses infecting eukaryotic cells. In this paper we discuss recent advances in understanding alternative ways to initiate translation across eukaryotic organisms.

scholarly journals The internal ribosome entry site of the Dengue virus mRNA is active when cap-dependent translation initiation is inhibited.

2020 ◽  
Author(s):  
Leandro Fernández-García ◽  
Jenniffer Angulo ◽  
Hade Ramos ◽  
Aldo Barrera ◽  
Karla Pino ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Dengue Virus ◽  
Translation Initiation ◽  
Internal Ribosome Entry Site ◽  
Entry Site ◽  
Internal Ribosome Entry ◽  
Mouth Disease Virus ◽  
Independent Mechanism ◽  
In Cells

Dengue virus (DENV) is an enveloped, positive-sense, single-stranded RNA virus belonging to the Flaviviridae family. Translation initiation of the DENV mRNA can occur following a cap-dependent or a cap-independent mechanism. Two non-mutually exclusive cap-independent mechanisms of translation initiation have been described for the DENV mRNA. The first corresponds to a 5′end-dependent internal ribosome entry site (IRES)-independent mechanism, while the second relies on IRES-dependent initiation. In this report, we study the recently discovered DENV IRES. Results show that the DENV IRES is functional in the rabbit reticulocyte (RRL) in vitro translation system. In accordance, the activity of DENV IRES was resistant to the cleavage of eIF4G by the Foot-and-mouth disease virus leader protease in RRL. In cells, the DENV IRES exhibited only a marginal activity under standard culture conditions. The DENV IRES showed weak activity in HEK 293T cells; however, the DENV IRES activity was significantly enhanced in HEK 293T cells expressing the Human rhinovirus 2A protease. These findings suggest that the DENV IRES enables viral protein synthesis under conditions that suppress canonical translation initiation. IMPORTANCE Dengue virus (DENV), the etiological agent of Dengue, a febrile and hemorrhagic disease, infects millions of people per year in tropical and subtropical countries. When infecting cells, DENV induces stress conditions known to inhibit canonical protein synthesis. Under these conditions, DENV mRNA thrives using non-canonical modes of translation initiation. In this study, we characterize the mechanism dependent upon an internal ribosome entry site (IRES). Herein, we describe the activity of the DENV IRES in vitro and cells. We show that in cells, DENV IRES enables the viral mRNA to translate under conditions that suppress canonical translation initiation.

scholarly journals Functional Insights into the Adjacent Stem-Loop in Honey Bee Dicistroviruses That Promotes Internal Ribosome Entry Site-Mediated Translation and Viral Infection

2017 ◽  
Vol 92 (2) ◽  
Author(s):  
Hilda H. T. Au ◽  
Valentina M. Elspass ◽  
Eric Jan
Keyword(s):  
Protein Synthesis ◽  
Virus Infection ◽  
Honey Bee ◽  
Internal Ribosome Entry Site ◽  
Viral Protein ◽  
Entry Site ◽  
Viral Protein Synthesis ◽  
Stem Loop ◽  
Internal Ribosome Entry ◽  
Paralysis Virus

ABSTRACTAll viruses must successfully harness the host translational apparatus and divert it toward viral protein synthesis. Dicistroviruses use an unusual internal ribosome entry site (IRES) mechanism whereby the IRES adopts a three-pseudoknot structure that accesses the ribosome tRNA binding sites to directly recruit the ribosome and initiate translation from a non-AUG start site. A subset of dicistroviruses, including the honey bee Israeli acute paralysis virus (IAPV), encode an extra stem-loop (stem-loop VI [SLVI]) 5′ adjacent to the intergenic region (IGR) IRES. Previously, the function of this additional stem-loop was unknown. Here, we provide mechanistic and functional insights into the role of SLVI in IGR IRES translation and in virus infection. Biochemical analyses of a series of mutant IRESs demonstrated that SLVI does not function in ribosome recruitment but is required for proper ribosome positioning on the IRES to direct translation. Using a chimeric infectious clone derived from the related cricket paralysis virus, we showed that the integrity of SLVI is important for optimal viral translation and viral yield. Based on structural models of ribosome-IGR IRES complexes, SLVI is predicted to be in the vicinity of the ribosome E site. We propose that SLVI of IAPV IGR IRES functionally mimics interactions of an E-site tRNA with the ribosome to direct positioning of the tRNA-like domain of the IRES in the A site.IMPORTANCEViral internal ribosome entry sites are RNA elements and structures that allow some positive-sense monopartite RNA viruses to hijack the host ribosome to start viral protein synthesis. We demonstrate that a unique stem-loop structure is essential for optimal viral protein synthesis and for virus infection. Biochemical evidence shows that this viral stem-loop RNA structure impacts a fundamental property of the ribosome to start protein synthesis.

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