scholarly journals Targeting Viral mRNA Translation Control as a New Concept for Anti-Virus Therapeutic Strategies

2021 ◽  
Vol 2 (2) ◽  
Keyword(s):  
Mrna Translation ◽  
Therapeutic Strategies ◽  
Viral Mrna ◽  
Translation Control

scholarly journals Ionizing Radiation and Translation Control: A Link to Radiation Hormesis?

2020 ◽  
Vol 21 (18) ◽  
pp. 6650
Author(s):  
Usha Kabilan ◽  
Tyson E. Graber ◽  
Tommy Alain ◽  
Dmitry Klokov
Keyword(s):  
Protein Synthesis ◽  
Ionizing Radiation ◽  
Molecular Mechanisms ◽  
Low Dose ◽  
Mrna Translation ◽  
Cellular Responses ◽  
Translation Control ◽  
Cis Acting ◽  
Radiation Hormesis ◽  
Downstream Signaling

Protein synthesis, or mRNA translation, is one of the most energy-consuming functions in cells. Translation of mRNA into proteins is thus highly regulated by and integrated with upstream and downstream signaling pathways, dependent on various transacting proteins and cis-acting elements within the substrate mRNAs. Under conditions of stress, such as exposure to ionizing radiation, regulatory mechanisms reprogram protein synthesis to translate mRNAs encoding proteins that ensure proper cellular responses. Interestingly, beneficial responses to low-dose radiation exposure, known as radiation hormesis, have been described in several models, but the molecular mechanisms behind this phenomenon are largely unknown. In this review, we explore how differences in cellular responses to high- vs. low-dose ionizing radiation are realized through the modulation of molecular pathways with a particular emphasis on the regulation of mRNA translation control.

scholarly journals The Role of Translation Initiation Regulation in Haematopoiesis

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Godfrey Grech ◽  
Marieke von Lindern
Keyword(s):  
Gene Expression ◽  
Translation Initiation ◽  
Translational Control ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Regulation Of Gene Expression ◽  
Mrna Translation ◽  
Translation Control ◽  
Haematological Disorders

Organisation of RNAs into functional subgroups that are translated in response to extrinsic and intrinsic factors underlines a relatively unexplored gene expression modulation that drives cell fate in the same manner as regulation of the transcriptome by transcription factors. Recent studies on the molecular mechanisms of inflammatory responses and haematological disorders indicate clearly that the regulation of mRNA translation at the level of translation initiation, mRNA stability, and protein isoform synthesis is implicated in the tight regulation of gene expression. This paper outlines how these posttranscriptional control mechanisms, including control at the level of translation initiation factors and the role of RNA binding proteins, affect hematopoiesis. The clinical relevance of these mechanisms in haematological disorders indicates clearly the potential therapeutic implications and the need of molecular tools that allow measurement at the level of translational control. Although the importance of miRNAs in translation control is well recognised and studied extensively, this paper will exclude detailed account of this level of control.

scholarly journals Adenovirus E1B proteins are required for accumulation of late viral mRNA and for effects on cellular mRNA translation and transport.

1985 ◽  
Vol 5 (10) ◽  
pp. 2552-2558 ◽  
Author(s):  
L E Babiss ◽  
H S Ginsberg ◽  
J E Darnell
Keyword(s):  
Mrna Translation ◽  
Mutant Virus ◽  
Viral Mrna ◽  
Mrna Synthesis ◽  
Mrna Transport ◽  
Normal Delivery ◽  
Single Function ◽  
Infected Cells ◽  
Steady State Levels ◽  
Adenovirus E1b

Late in adenovirus infection, large amounts of viral mRNA accumulate while cell mRNA transport and translation decrease. Viruses deleted in the E1B region of type 5 adenovirus do not produce the same outcome: (i) viral mRNA synthesis by the mutants is normal, delivery to the cytoplasm is 50 to 75% of normal, but steady-state levels of viral mRNA are decreased 10-fold; (ii) cell mRNA synthesis and transport continue normally in the mutant virus-infected cell; and (iii) translation of preexisting cell mRNA which is disrupted in wild-type infection remains normal in mutant-virus-infected cells. Thus E1B proteins are required for accumulation of virus mRNA and for induction of the failure of host cell mRNA transport and translation. If a single function is involved, by inference the transport and some aspect of translation of mRNAs could be linked.

scholarly journals The 5′ Untranslated Region of the Major Immediate Early mRNA Is Necessary for Efficient Human Cytomegalovirus Replication

2018 ◽  
Vol 92 (7) ◽  
Author(s):  
Kyle C. Arend ◽  
Erik M. Lenarcic ◽  
Nathaniel J. Moorman
Keyword(s):  
Protein Expression ◽  
Human Cytomegalovirus ◽  
Untranslated Region ◽  
Mrna Translation ◽  
Lytic Replication ◽  
Immediate Early ◽  
Translation Control ◽  
Positive Role ◽  
Free System ◽  
Hcmv Replication

ABSTRACTThe human cytomegalovirus (HCMV) immediate early 1 (IE1) and IE2 proteins are critical regulators of virus replication. Both proteins are needed to efficiently establish lytic infection, and nascent expression of IE1 and IE2 is critical for reactivation from latency. The regulation of IE1 and IE2 protein expression is thus a central event in the outcome of HCMV infection. Transcription of the primary transcript encoding both IE1 and IE2 is well studied, but relatively little is known about the posttranscriptional mechanisms that control IE1 and IE2 protein synthesis. The mRNA 5′ untranslated region (5′ UTR) plays an important role in regulating mRNA translation. Therefore, to better understand the control of IE1 and IE2 mRNA translation, we examined the role of the shared 5′ UTR of the IE1 and IE2 mRNAs (MIE 5′ UTR) in regulating translation. In a cell-free system, the MIE 5′ UTR repressed translation, as predicted based on its length and sequence composition. However, in transfected cells we found that the MIE 5′ UTR increased the expression of a reporter gene and enhanced its association with polysomes, demonstrating that the MIE 5′ UTR has a positive role in translation control. We also found that the MIE 5′ UTR was necessary for efficient IE1 and IE2 translation during infection. Replacing the MIE 5′ UTR with an unstructured sequence of the same length decreased IE1 and IE2 protein expression despite similar levels of IE1 and IE2 mRNA and reduced the association of the IE1 and IE2 mRNAs with polysomes. The wild-type MIE 5′-UTR sequence was also necessary for efficient HCMV replication. Together these data identify the shared 5′ UTR of the IE1 and IE2 mRNAs as an important regulator of HCMV lytic replication.IMPORTANCEThe HCMV IE1 and IE2 proteins are critical regulators of HCMV replication, both during primary infection and during reactivation from viral latency. Thus, defining factors that regulate IE1 and IE2 expression is important for understanding the molecular events controlling the HCMV replicative cycle. Here we identify a positive role for the MIE 5′ UTR in mediating the efficient translation of the IE1 and IE2 mRNAs. This result is an important advance for several reasons. To date, most studies of IE1 and IE2 regulation have focused on defining events that regulate IE1 and IE2 transcription. Our work reveals that in addition to the regulation of transcription, IE1 and IE2 are also regulated at the level of translation. Therefore, this study is important in that it identifies an additional layer of regulation controlling IE1 and IE2 expression and thus HCMV pathogenesis. These translational regulatory events could potentially be targeted by novel antiviral therapeutics that limit IE1 and IE2 mRNA translation and thus inhibit lytic replication or prevent HCMV reactivation.

scholarly journals Poliovirus 2APro Increases Viral mRNA and Polysome Stability Coordinately in Time with Cleavage of eIF4G

2008 ◽  
Vol 82 (12) ◽  
pp. 5847-5859 ◽  
Author(s):  
Brian J. Kempf ◽  
David J. Barton
Keyword(s):  
De Novo ◽  
Mrna Translation ◽  
Viral Mrna ◽  
Site Mutation ◽  
Initiation Factors ◽  
Eukaryotic Initiation Factors ◽  
Messenger Ribonucleoprotein ◽  
Infected Cells ◽  
The Stability ◽  
Polysome Stability

ABSTRACT Poliovirus (PV) 2A protease (2APro) cleaves eukaryotic initiation factors 4GI and 4GII (eIF4GI and eIF4GII) within virus-infected cells, effectively halting cap-dependent mRNA translation. PV mRNA, which does not possess a 5′ cap, is translated via cap-independent mechanisms within viral protease-modified messenger ribonucleoprotein (mRNP) complexes. In this study, we determined that 2APro activity was required for viral polysome formation and stability. 2APro cleaved eIF4GI and eIF4GII as PV polysomes assembled. A 2ACys109Ser (2APro with a Cys109Ser mutation) protease active site mutation that prevented cleavage of eIF4G coordinately inhibited the de novo formation of viral polysomes, the stability of viral polysomes, and the stability of PV mRNA within polysomes. 2ACys109Ser-associated defects in PV mRNA and polysome stability correlated with defects in PV mRNA translation. 3CPro activity was not required for viral polysome formation or stability. 2APro-mediated cleavage of eIF4G along with poly(rC) binding protein binding to the 5′ terminus of uncapped PV mRNA appear to be concerted mechanisms that allow PV mRNA to form mRNP complexes that evade cellular mRNA degradation machinery.

Transcriptional and translational events during reovirus infection

1988 ◽  
Vol 66 (8) ◽  
pp. 803-812 ◽  
Author(s):  
Guy Lemay
Keyword(s):  
Protein Synthesis ◽  
Host Cell ◽  
Mrna Translation ◽  
Cell Membrane Permeability ◽  
Cell Protein ◽  
Viral Mrna ◽  
Genomic Rna ◽  
Host Cell Protein ◽  
Outer Capsid ◽  
Viral Genomic Rna

This short review focuses on the mechanisms involved in transcription and translation in mouse L cells infected with reoviruses. The viral genomic RNA (double-stranded), retained in the inner capsid following removal of the outer capsid of the infecting virion, is transcribed by a viral polymerase. The synthesized viral mRNA is blocked at the 5′ end by a cap structure similar to the cap structure of cellular mRNA but synthesized by the viral enzymes of the inner capsid. This viral mRNA is also used as the first strand and template for the synthesis of the second strand of viral genomic RNA; the newly replicated genome is retained in an inner capsid structure to generate the progeny subviral particles. These particles are active at the transcriptional level but do not synthesize the cap, owing to the absence of the guanylyltransferase activity involved in the formation of this structure. The uncapped mRNA, or late viral mRNA, constitutes the bulk part of viral mRNA. The transcription of the viral genome is finally arrested upon addition of outer capsid proteins to obtain a mature virion. During viral multiplication, there is a gradual inhibition of host-cell protein synthesis, concomitant with stimulation of late viral mRNA translation. The two phenomena are apparently distinct. Furthermore, the inhibition of host-cell protein synthesis has been shown to be dispensable for normal virus multiplication; however, it might accelerate it. The mechanisms responsible for inhibition are still unclear but might involve modifications in the activity of cellular cap-binding proteins. This last point suggests an analogy with poliovirus infection; the two systems are thus briefly compared. Possible significance of the absence of a poly(A) tract at the 3′ end of reovirus mRNA, in contrast to the occurrence of such a sequence at the end of cellular mRNA, is also examined. Different models involving cap discrimination, competition between mRNAs, or alteration of cell membrane permeability have been proposed to explain the events observed at the translational level in reovirus-infected cells. These different models are compared. Finally, recent data implicating the viral sigma 3 capsid protein in efficient translation of late viral mRNA are discussed.

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