Review
Regulation Mechanisms of Viral IRES-Driven Translation

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For efficient viral IRES-dependent translation and rapid adaption, RNA viruses redistribute IRES trans-acting factors (ITAFs) by either forcing leakage from the nucleus, or cleaving the NLS, and the cleavage of eIF4G and ITAFs by viral proteases is a critical mechanism of RNA viruses to regulate IRES-dependent translation

Post-translational modification of ITAFs represents alternative strategies for viruses to utilize cellular resources for better fitness.

Elucidation of viral IRES-mediated translation not only helps the development of antiviral strategies, but also provides an opportunity for the therapeutic application of genetically modified viruses, such as an oncolytic virus.

Internal ribosome entry sites (IRESs) can be found in the mRNA of many viruses as well as in cellular genes involved in the stress response, cell cycle, and apoptosis. IRES-mediated translation can occur when dominant cap-dependent translation is inhibited, and viruses can take advantage of this to subvert host translation machinery. In this review, we focus on the four major types of IRES identified in RNA viruses, and outline their distinct structural properties and requirements of translational factors. We further discuss auxiliary host factors known as IRES trans-acting factors (ITAFs), which are involved in the modulation of optimal IRES activity. Currently known strategies employed by viruses to harness ITAFs and regulate IRES activity are also highlighted.

Section snippets

Viruses Take Advantage of IRESs in Host Cells

Due to limited coding capacity in their genomes, viruses have evolved various ways to hijack key steps in the cellular gene expression pathway, among which the commandeering of translation processes can arguably be considered a critical step for viral propagation [1]. Based on the mechanism of translation initiation, which also serves as the rate-limiting step, cellular translation pathways can be divided into cap- and IRES-dependent translation [2]. In eukaryotes, protein-coding messenger RNAs

Viral Manipulation of Cap-Dependent Translation

Prior to discussing how RNA viruses initiate IRES-dependent translation, it is necessary to compare the differences and interconnections between the two translation mechanisms described. Cap-dependent translation can be divided into four steps: initiation, elongation, termination, and ribosome recycling, with each step mediated by a distinct set of regulatory factors. Given its importance as the rate-limiting step, the initiation mechanism has been extensively studied (reviewed in [10]), and

Viral Utilization of IRES-Dependent Translation

The IRES element was first identified in the late 1980s from the 5ʹ-UTR of the poliovirus (PV) and encephalomyocarditis virus (EMCV) genomes; both viruses are members of the picornavirus family 7, 8. Since then IRES elements have been shown to exist in all genera of Picornaviridae [15]. Besides RNA viruses, IRES elements have also been widely identified in other viruses (retroviruses and DNA viruses etc.) as well as cellular mRNAs 3, 6, 16, 17. However, the structure and function of cellular

ITAF Modulation of IRES-Mediated Translation during Infection

Instead of binding to ribosome directly, not all of viral IRESs were able to drive translation properly in rabbit reticulate lysates, but this was resolved after human cell lysates were supplemented, indicating the critical role of cellular proteins to the regulation of IRES activity. Since PTB and La were identified as ITAFs 76, 77, many proposed ITAFs have been reported (Table 1). Most, if not all, of these ITAFs are RNA-processing factors containing multiple copies of RNA-binding domains 3, 4

Concluding Remarks and Future Perspectives

In this review, we presented the latest understanding regarding the mechanisms involved in viral IRES-driven translation. The inherent structure-based properties of the IRESs suggest that these elements can serve as ideal platforms for the development of antiviral drugs [52]. Antisense nucleotides specifically targeting IRES elements have been developed, but issues of inefficient delivery and off-target effects remain to be overcome [9]. However, other ways of utilizing the IRES for viral

Acknowledgments

Due to the limitation of length, the authors apologize to those colleagues whose work could not be cited. This work was financially supported by a grantfrom the Chang Gung Memorial Hospital (CMRPD1D0313), Taoyuan, Taiwan.

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    These authors contributed equally to this work.

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