Role of RNA Structure Motifs in IRES-Dependent Translation Initiation of the Coxsackievirus B3: New Insights for Developing Live-Attenuated Strains for Vaccines and Gene Therapy

Souii, Amira; M’hadheb-Gharbi, Manel Ben; Gharbi, Jawhar

doi:10.1007/s12033-013-9674-4

Cited by 14 publications

(14 citation statements)

References 219 publications

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“…Structurally, iCVB3 can be divided into seven domains 33 , beginning with domain I containing a cloverleaf structure thought to be critical for viral replication 34 . Domains II-V have also been reported to interact with multiple IRES trans-activating factors (ITAFs) [35][36][37] , whereas domain VI hosts an AUG upstream of the true translation initiation site that recruits the 43S ribosomal pre-initiation complex [37][38][39] .…”

Section: A Full-length Viral Ires Is Critical For Strong Translation ...mentioning

confidence: 99%

Engineering circular RNA for enhanced protein production

et al. 2022

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Circular RNAs (circRNAs) are stable and prevalent RNAs in eukaryotic cells that arise from back-splicing. Synthetic circRNAs and some endogenous circRNAs can encode proteins, raising the promise of circRNA as a platform for gene expression. In this study, we developed a systematic approach for rapid assembly and testing of features that affect protein production from synthetic circRNAs. To maximize circRNA translation, we optimized five elements: vector topology, 5′ and 3′ untranslated regions, internal ribosome entry sites and synthetic aptamers recruiting translation initiation machinery. Together, these design principles improve circRNA protein yields by several hundred-fold, provide increased translation over messenger RNA in vitro, provide more durable translation in vivo and are generalizable across multiple transgenes.

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Section: A Full-length Viral Ires Is Critical For Strong Translation ...mentioning

confidence: 99%

Engineering circular RNA for enhanced protein production

et al. 2022

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“…This regulation is mediated in large part, through the methylation of hnRNP A1 (Figures 4 and 5). Different IRES structures recruit different cohorts of IRES transacting factors (ITAF) (59,60). hnRNP A1 is a ITAF, although it is unclear if it regulates translation from all IRESes, or just a subset.…”

Section: Discussionmentioning

confidence: 99%

PRMT5 regulates IRES-dependent translation via methylation of hnRNP A1

2017

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The type II arginine methyltransferase PRMT5 is responsible for the symmetric dimethylation of histone to generate the H3R8me2s and H4R3me2s marks, which correlate with the repression of transcription. However, the protein level of a number of genes (MEP50, CCND1, MYC, HIF1a, MTIF and CDKN1B) are reported to be downregulated by the loss of PRMT5, while their mRNA levels remain unchanged, which is counterintuitive for PRMT5's proposed role as a transcription repressor. We noticed that the majority of the genes regulated by PRMT5, at the posttranscriptional level, express mRNA containing an internal ribosome entry site (IRES). Using an IRES-dependent reporter system, we established that PRMT5 facilitates the translation of a subset of IRES-containing genes. The heterogeneous nuclear ribonucleoprotein, hnRNP A1, is an IRES transacting factor (ITAF) that regulates the IRES-dependent translation of Cyclin D1 and c-Myc. We showed that hnRNP A1 is methylated by PRMT5 on two residues, R218 and R225, and that this methylation facilitates the interaction of hnRNP A1 with IRES RNA to promote IRES-dependent translation. This study defines a new role for PRMT5 regulation of cellular protein levels, which goes beyond the known functions of PRMT5 as a transcription and splicing regulator.

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“…Cell lysate collected at different time point (interval of 3 h and up to 12 h of infection) were analyzed using Western blotting. As shown in Figure 5C , the synthesis of viral protein was completely not noticeable until the time point between 3 and 6 hpi; presumably, the transcription of viral RNA, which is the first intracellular step during CVB3 replication ( Souii et al, 2013 ), has been initiated earlier before this time point. In culture medium supplemented with EHX, the synthesis of 3D protein was almost completely blocked until time point between 6 and 9 hpi.…”

Section: Resultsmentioning

confidence: 93%

Novel Antiviral Activity of Ethyl 3-Hydroxyhexanoate Against Coxsackievirus B Infection

et al. 2022

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Coxsackievirus group B (CVB) is a member of the genus Enterovirus in the family Picornaviridae. CVB infection has been implicated as a major etiologic agent of viral myocarditis, dilated cardiomyopathy, meningitis, and pancreatitis among children and young adults. Until date, no antiviral agent has been licensed for the treatment of Coxsackievirus infection. In an effort to identify antiviral agents against diseases caused by the CVB, we found that ethyl 3-hydroxyhexanoate (EHX), a volatile compound present in fruits and food additives, is a potent antiviral compound. In this study, we demonstrated that EHX treatment significantly inhibits CVB replication both in vivo and in vitro. Furthermore, EHX possesses antiviral activity at 50% effective concentration (EC50) of 1.2 μM and 50% cytotoxicity (CC50) of 25.6 μM, yielding a selective index (SI) value as high as 20.8. Insights into the mechanism of antiviral activity of EHX showed that it acts at the step of viral RNA replication. Since EHX has received approval as food additives, treatment of CVB-related infections with EHX might be a safe therapeutic option and may be a promising strategy for the development of semi-synthetic antiviral drugs for viral diseases.

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Role of RNA Structure Motifs in IRES-Dependent Translation Initiation of the Coxsackievirus B3: New Insights for Developing Live-Attenuated Strains for Vaccines and Gene Therapy

Cited by 14 publications

References 219 publications

Engineering circular RNA for enhanced protein production

Engineering circular RNA for enhanced protein production

PRMT5 regulates IRES-dependent translation via methylation of hnRNP A1

Novel Antiviral Activity of Ethyl 3-Hydroxyhexanoate Against Coxsackievirus B Infection

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