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Order Picornavirales
Published in Paul Pumpens, Peter Pushko, Philippe Le Mercier, Virus-Like Particles, 2022
Paul Pumpens, Peter Pushko, Philippe Le Mercier
Figure 27.2 shows the genomic structure of the Picornavirales families and genera, which are most involved into the 3D and VLP studies. In brief, the Caliciviridae members possess monopartite RNA genome of 7.4–8.3 kb, with a 5′-terminal genome-linked virus protein VPg of 10–15 kDa and 3′-terminal poly(A) tract. The genome is organized into either two or three major ORFs, while a further ORF4 of murine norovirus (MNV) encodes virulence factor VF1 (Vinjé et al. 2019). The Picornaviridae genomic RNA, ranging in size from 6.7 kb to 10.1 kb, commonly contains a single large ORF coding for a polyprotein, whereas a typical picornavirus genome encodes three or four capsid proteins and at least seven nonstructural proteins. The IRES element and the 2A genome region may have been exchanged between the genera. There may be more than one protein produced from the L or 2A genome regions, as well as multiple copies of 3B in the picornavirus genome (Zell et al. 2017). The Secoviridae genomic RNA of total 9.0–13.7 kb size could be mono- or bipartite RNA, as mentioned earlier for CPMV. The genomic RNAs are covalently linked to a small viral genome-linked protein VPg of 2–4 kDa at their 5’ end and have a 3’-terminal poly(A) tract. Each RNA encodes, in most of the cases, a single polyprotein (Thompson et al. 2017).
Nitric Oxide as a Signaling Molecule in the Systemic Inflammatory Response to LPS
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
Only recently has it become clear that NO can also regulate gene expression by a similar mechanism. This is illustrated by its effects on iron metabolism in mammalian cells. The iron-regulated biosynthesis of the transferrin receptor and ferritin, two proteins that control iron uptake and storage, is dependent on consensus iron-response elements (IRE) located in the 3′ or 5′ untranslated regions of their mRNAs. Two mammalian iron regulatory proteins, IRP-1 and IRP-2, that exist in all vertebrate tissues bind to the IREs and have been shown to be responsive to oxidative stress (16). For example, H2O2 can induce IRP-1 binding to the IRE of ferritin mRNA, which inhibits its translation efficiency and reduces intracellular ferritin levels (76). Similar high-affinity binding of IRP-1 to the IREs in the 3′ untranslated region of transferrin receptor mRNA reduces nucleolytic degradation of this message (77–79). Together, these two effects of H2O2 increase iron up-take and decrease the ability of the cell to store intra-cellular iron in a bound form, thus increasing the intracellular pool of free iron.
Hepatitis A Virus
Published in Dongyou Liu, Handbook of Foodborne Diseases, 2018
Following attachment to the hepatocyte, the viral particles are internalized through a receptor-mediated endocytosis, followed by uncoating and release of single-stranded viral RNA in cell cytoplasm. Upon release into the cell cytoplasm, the IRES located in the 5′-UTR of HAV RNA directs the host ribosomal machinery to promote cap-independent translation of the viral genome, producing a large polyprotein. This protein is then cleaved by viral and host proteases into several functional precursor and mature proteins. The nonstructural proteins join the replication complex for synthesis of new positive-sense RNAs, and the structural proteins assemble into new virion capsids.
Locked and loaded: engineering and arming oncolytic adenoviruses to enhance anti-tumor immune responses
Published in Expert Opinion on Biological Therapy, 2022
To circumvent this problem and conserve space, internal ribosome entry sites (IRESs) from RNA viruses can be utilized. IRESs are 300–600 bp sequences derived from RNA viruses that will allow ribosomes to be recruited and initiate protein translation without 5ʹcap recognition. Placing IRES upstream of the second cDNA will allow polycistronic gene expressions [76]. IRESs have been used to co-express transgenes on the same transcripts as E1A, E2B, and fiber [77]. Head-to-head comparisons of IRESs in these locations showed that fiber-linked IRES transcripts had the strongest expression, although this expression was delayed [77]. Intermediate levels of expression were observed with E2B-linked IRES transcripts, while E1A-linked IRES transcripts have the lowest luciferase expression level [77]. Although IRES elements eliminate the need for a second set of enhancer/promoters and polyA sequences, they are still relatively long and consume precious viral genome space. In addition, typically weaker expression of the second cDNA in an IRES cassette is observed. This can vary from gene to gene, so the expression of genes in IRES cassettes has to be measured empirically.
Research Progress of circRNAs in Inflammatory Mechanisms of Diabetic Retinopathy: An Emerging Star with Potential Therapeutic Targets
Published in Current Eye Research, 2022
Shuai He, Chufeng Gu, Tong Su, Qinghua Qiu
Because of the special structure of circRNAs without a 5ʹ cap or a 3ʹ poly A tail, which is indispensable for classical cap-dependent translation, circRNAs have been suggested to be able to be translated in cap-independent manners.46 On the one hand, there are available sequences serving as internal ribosome entry sites (IRESs) of circRNAs to facilitate direct combination with the ribosome or the initiation factors in the course of translation.47–49 To date, only a small number of circRNAs such as circ-FBXW7, circPINTexon2 and circ-SHPRH have been reported to bind with ribosomes for translation.50,51 Specifically, Yang, Y. et al. proved that the peptides FBXW-185aa, PINT87aa and SHPRH-146aa originated from circ-FBXW7, circPINTexon2 and circ-SHPRH, respectively and were considered to inhibit tumor biogenesis in human glioblastoma.52,53 This translation mechanism of circRNAs shares the same initiation codons with the hosting mRNAs, which enables these polypeptides to be derived from circRNAs to compete with mRNA-encoded proteins and affect biological function.51 On the other hand, circRNA translation can also be induced by m6A modification in the 5′ untranslated region (UTR),54,55 proved by the fact that m6A demethylase fat mass hindered the process of translation and decreased the efficiency.56
An overview of rational design of mRNA-based therapeutics and vaccines
Published in Expert Opinion on Drug Discovery, 2021
Kenneth K.W. To, William C.S. Cho
Messenger RNA untranslated regions (UTR), including the 5ʹUTR and 3ʹUTR, contain multiple regulatory elements to control the stability and translation of mRNA. The 5ʹUTR plays an important role in controlling protein translation efficiency because it represents the binding site for the preinitiation complex initiation of protein translation [65–67]. The binding of eukaryotic initiation factor-4A (eIF4A) to the 5ʹUTR is crucial to unwind the secondary structure of mRNA before protein translation can occur [65]. The secondary structure of the 5ʹUTR also affects the binding of eIF1A to mRNA [68]. On the other hand, most eukaryotic mRNAs contain mRNA degradation signals in their 3ʹUTR, which regulate mRNA stability. AU-rich sequences in mRNA 3ʹUTR are known to participate in the removal of the poly(A) tail during mRNA degradation [69]. Therefore, half-life of the labile mRNAs could be increased when their AU-rich sequences are replaced with 3ʹUTR sequences from more stable mRNA [70]. Another important mRNA stability-regulating sequence within the 3ʹUTR is called the iron-responsive elements (IREs) [71]. IREs have also been reported to regulate mRNA translation [71].