Picornavirus IRES elements: RNA structure and host protein interactions

doi:10.1016/j.virusres.2015.01.012

Virus Research

Volume 206, 3 August 2015, Pages 62-73

https://doi.org/10.1016/j.virusres.2015.01.012 Get rights and content

Highlights

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Picornavirus infection triggers host factors modification impacting on cellular gene expression.
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Picornavirus RNA translation is governed by IRES elements which are resistant to cap-dependent inactivation.
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Diversity of picornavirus IRES RNA structural organization.
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Implication of host RNA-binding proteins in picornavirus protein synthesis.

Abstract

Internal ribosome entry site (IRES) elements were discovered in picornaviruses. These elements are cis-acting RNA sequences that adopt diverse three-dimensional structures and recruit the translation machinery using a 5′ end-independent mechanism assisted by a subset of translation initiation factors and various RNA binding proteins termed IRES transacting factors (ITAFs). Many of these factors suffer important modifications during infection including cleavage by picornavirus proteases, changes in the phosphorylation level and/or redistribution of the protein from the nuclear to the cytoplasm compartment. Picornavirus IRES are amongst the most potent elements described so far. However, given their large diversity and complexity, the mechanistic basis of its mode of action is not yet fully understood. This review is focused to describe recent advances on the studies of RNA structure and RNA–protein interactions modulating picornavirus IRES activity.

Section snippets

Picornavirus genome organization

Picornaviruses are non-enveloped positive strand RNA viruses with an icosahedral capsid, which cause important diseases in humans and animals, such as common-cold illnesses, polio, or chronic livestock infections. Picornaviruses are currently classified into 26 genera (Table 1), and unassigned species continue to be described (http://www.picornaviridae.com/). It is widely accepted that the entire life cycle of all picornaviruses occurs in the cytoplasm of the infected cell. Their genome

Features of the picornavirus untranslated region

The genomic RNA of picornaviruses differs from the cellular RNAs in two critical features. First, they do not contain a cap structure at the 5′ end. Instead, a viral protein (VPg) is covalently linked to the 5′UTR. Second, an internal cis-acting region within the 5′UTR, designated internal ribosome entry site (IRES) element, governs the recruitment of the ribosomal subunits using a process independent of the cap-binding protein eIF4E.

IRES elements were initially reported in poliovirus (PV) and

Picornavirus-induced modification of host factors

Picornavirus infections exert a strong influence on the host gene expression as a result of the proteolysis of specific host factors induced by the 2A, L and 3C picornavirus proteases (Table 2). Indeed, as a consequence of the cleavage of cellular proteins, several processes critical for cell viability are profoundly altered. This is noticed at the level of transcription, mRNA processing, nucleo-cytoplasmic transport, translation, or RNA granules composition. Among other proteins, proteolysis

Translation initiation in eukaryotic cells

Most cellular mRNAs initiate translation by a mechanism that depends on the recognition of the m⁷G(5′)ppp(5′)N structure (termed cap) located at the 5′ end of mRNAs (Sonenberg and Hinnebusch, 2009). In these RNAs, the 5′ cap structure is recognized by eIF4F, a trimeric factor composed of the cap-binding protein eIF4E, the scaffolding protein eIF4G, and the RNA helicase eIF4A (Fig. 3A). The cap-binding capacity of eIF4E is regulated by phosphorylation levels of eIF4E-binding proteins (eIF4E-BP

IRES-dependent translation initiation in picornavirus RNAs

As mentioned above, cap-dependent translation initiation is inhibited in picornavirus-infected cells. In addition to eIF4G and PABP proteolysis, eIF4E is targeted in EMCV and PV infected cells through dephosphorylation of 4E-BPs (Gingras et al., 1996). Hypophosphorylated 4E-BPs bind strongly to eIF4E preventing the binding to eIF4G, and thus, inactivating cap-dependent translation. These adverse situations, however, allow translation of picornavirus RNAs that evade translation shutdown taking

RNA–protein interactions involved in picornavirus IRES activity

In addition to the eIFs described in the above sections, auxiliary factors termed IRES-transacting factors (ITAFs) contribute to modulate (either stimulate or repress) IRES activity. Early studies demonstrated that poliovirus IRES activity in reticulocyte lysates was dependent on the addition of factors present in HeLa cells (Dorner et al., 1984). More recently it has been shown that ITAFs stimulate the assembly of 48S complex in vitro on the cardio- and aphthovirus IRES (Andreev et al., 2007,

Implications of long-range 5′–3′ viral RNA interactions on IRES activity

On the opposite end of the picornavirus genome, the 3′UTR plays a critical role in virus multiplication (Duque and Palmenberg, 2001, Melchers et al., 1997, Saiz et al., 2001, Todd et al., 1997). This region harbors a heterogeneous sequence, ranging between 42 nts in HRV and 317 nts in DHAV, in addition to a relative short polyA tail. Enterovirus 3′UTR RNA structure models suggest the presence of two stem-loops, with a kissing loop predicted in some instances (Pilipenko et al., 1996, Wang et al.,

Conclusions and perspectives

The understanding of RNA structure organization and host protein interaction relevant for viral IRES elements function has made considerable progress in recent years (Hashem et al., 2013, Plank and Kieft, 2012). The three-dimensional structure of picornavirus IRES elements is yet unknown despite being the first functional IRES elements ever described, but progress in this direction has being made (Jung and Schlick, 2014, King et al., 2013, Lozano et al., 2014). Noteworthy, understanding the

Acknowledgements

This work was supported by grants BFU2011-25437 and CSD2009-00080 from MINECO, and by an Institutional grant from Fundación Ramón Areces.

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A number of viruses harbor their own IRESes, and can take advantage of the IRES-mediated translation to subvert host translation machinery (Lee et al., 2017). Picornaviral IRES elements can adopt diverse three-dimensional structures, and recruit the translation machinery using a 5′ end-independent mechanism, assisted by translation initiation factors and RNA binding proteins (Martínez-Salas et al., 2015). The picornaviral IRES elements are structurally classified into five types: type I, II, III, hepatitis C virus (HCV)-like and aichivirus-like IRESes (Lozano and Martínez-Salas, 2015).
Senecavirus A (SVA), formerly known as Seneca Valley virus, belongs to the genus Senecavirus in the family Picornaviridae. SVA has a single-stranded, positive-sense RNA genome, which is actually an mRNA that initiates translation via its own internal ribosome entry site (IRES). The SVA IRES has been demonstrated to be the hepatitis C virus (HCV)-like IRES, containing eight stem-loop domains: domain (D)II, DIIIa, DIIIb, DIIIc, DIIId1, DIIId2, DIIIe and DIIIf. In this study, stem-forming motifs (SFMs) in the eight domains were independently subjected to site-directed mutagenesis (SDM) to construct eight SVA minigenomes for dual-luciferase reporter assay. The result suggested that except the DII, the other seven domains were closely evolved in the IRES activity. Subsequently, a full-length SVA cDNA clone tagged with a reporter gene was genetically modified to construct eight SFM-mutated ones, separately transfected into BSR-T7/5 cells in an attempt to rescue replication-competent SVAs. Nevertheless, no virus was successfully rescued from its own cDNA clone, implying each of the putative domains necessary in SVA IRES for viral replication. Further, we attempted to rescue replication-competent SVA via pairwise transfection of cDNA clones. Out of 28 combinations of co-transfection, four were demonstrated to be able to rescue replication-competent SVAs. Sanger sequencing showed that all four viruses had the wild-type IRES genotype, suggesting the occurrence of putative copy-choice recombination between two IRES-modifying genomes.
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We conclude that prior to exponential viral protein production, 2Apro specifically targets eIF4G (likely by binding to the adjacent eIF3L) and Nup98, key players in regulating critical functions of host cells, rapidly destroying both proteins. eIF4G cleavage results in an arrest of host translation, preventing accumulation of new host proteins, and creating eIF4G cleavage products, which partake in internal ribosome entry site-mediated translation of the picornaviral genome and promotion of viral translation (78). Nup98 degradation largely abrogates a number of nuclear export pathways, including cellular mRNA export; together with eIF4G cleavage, these changes attenuate the ability of infected cells to mount an innate immune response.
Picornaviruses are small RNA viruses that hijack host cell machinery to promote their replication. During infection, these viruses express two proteases, 2A^pro and 3C^pro, which process viral proteins. They also subvert a number of host functions, including innate immune responses, host protein synthesis, and intracellular transport, by utilizing poorly understood mechanisms for rapidly and specifically targeting critical host proteins. Here, we used proteomic tools to characterize 2A^pro interacting partners, functions, and targeting mechanisms. Our data indicate that, initially, 2A^pro primarily targets just two cellular proteins: eukaryotic translation initiation factor eIF4G (a critical component of the protein synthesis machinery) and Nup98 (an essential component of the nuclear pore complex, responsible for nucleocytoplasmic transport). The protease appears to employ two different cleavage mechanisms; it likely interacts with eIF3L, utilizing the eIF3 complex to proteolytically access the eIF4G protein but also directly binds and degrades Nup98. This Nup98 cleavage results in only a marginal effect on nuclear import of proteins, while nuclear export of proteins and mRNAs were more strongly affected. Collectively, our data indicate that 2A^pro selectively inhibits protein translation, key nuclear export pathways, and cellular mRNA localization early in infection to benefit viral replication at the expense of particular cell functions.
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A viral protein (VPg) is covalently linked to the 5′ end of SVA genome that is infectious and functions as mRNA. The SVA 5′ UTR is an approximately 665-bp-long sequence, containing a hepatitis C virus (HCV)-like internal ribosome entry site (IRES) (Fig. 1B), which recruits ribosomal subunits using a process independent of the cap-binding protein, eukaryotic initiation factor (eIF) 4E (Martínez-Salas et al., 2015). The HCV-like IRES forms a defined secondary structure that contains two major hairpins, termed domain II and III (Chard et al., 2006; Easton et al., 2009).
The 5′ untranslated region (UTR) of Senecavirus A (SVA) harbors an internal ribosome entry site (IRES), in which a pseudoknot structure is upstream of start codon AUG. Wild-type SVAs have a highly conserved 13-nt-sequence between the pseudoknot stem II (PKS-II)-forming motif and the AUG. In this study, a single nucleotide was deleted one by one from the 13-nt-sequence within a wild-type SVA minigenome. The result showed that neither mono- nor multi-nucleotide deletions abolished the IRES activity. Furthermore, a single nucleotide was deleted one by one from the 13-nt-sequence within a full-length SVA cDNA clone. The result indicated that nucleotide-deleting SVAs could be rescued from 1- to 5-nt-deleting cDNA clones, whereas only the 1- and 2-nt-deleting viruses were genetically stable during nine serial passages in vitro. Additionally, only the 1-nt-deleting SVA showed similar growth kinetics to that of the wild-type virus, suggesting that the pseudoknot-AUG distance was crucial for SVA replication.
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Referring to other picornaviruses (Sun et al., 2016), the polyprotein precursor can be stepwisely cleaved into twelve polypeptides, namely the L, VP4, VP2, VP3, VP1, 2A, 2B, 2C, 3A, 3B, 3C and 3D. The SVA 5′ UTR is an approximately 665-bp-long sequence, containing a hepatitis C virus (HCV)-like internal ribosome entry site (IRES) (Fig. 1, IRES), which recruits ribosomal subunits using a process independent of the cap-binding protein, eukaryotic initiation factor (eIF) 4E (Martínez-Salas et al., 2015). The HCV-like IRES forms a defined secondary structure that contains two major hairpins, termed domain II and III (Chard et al., 2006; Easton et al., 2009).
Senecavirus A (SVA), formerly known as Seneca Valley virus, is classified into the genus Senecavirus in the family Picornaviridae. Mature virion harbors an approximately 7 300-nt-long, positive-sense, and single-stranded RNA genome, which contains 5′ and 3′ untranslated regions (UTRs). Internal ribosome entry site (IRES) is identified in the SVA 5′ UTR, and includes a RNA pseudoknot upstream of the start codon. This pseudoknot contains two stem structures, pseudoknot stem I and II (PKS-I and -II). The PKS-I is composed of two base-paired motifs (PKS-Ia and -Ib), between which there is an unpaired spacing (UpS). We reported previously that motif mutation in the PKS-II did not abolish the IRES activity, but interfered with SVA recovery from cDNA clone. In this study, we constructed five SVA minigenomes with point mutations in the PKS-I motif. Dual-luciferase reporter assay showed that motif mutations in PKS-I did not significantly interfere with the IRES activity to initiate protein expression. Correspondingly, we constructed five SVA cDNA clones with point mutations in the PKS-I motif. These genetically modified cDNA clones were separately transfected into BSR-T7/5 cells in attempting to rescue competent SVAs. However, only two viruses, namely PKS-Ia- and UpS-mutated recombinants, could be recovered from their individual cDNA clones. It can be concluded that the PKS-Ib is indispensable for viral growth.

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Picornavirus IRES elements: RNA structure and host protein interactions

Highlights

Abstract

Section snippets

Picornavirus genome organization

Features of the picornavirus untranslated region

Picornavirus-induced modification of host factors

Translation initiation in eukaryotic cells

IRES-dependent translation initiation in picornavirus RNAs

RNA–protein interactions involved in picornavirus IRES activity

Implications of long-range 5′–3′ viral RNA interactions on IRES activity

Conclusions and perspectives

Acknowledgements

Biochim. Biophys. Acta

Virology

Mol. Cell

Virus Res.

Virology

Virology

Virology

FEBS Lett.

Virology

Virus Res.

Virology

Virology

Virology

Biophys. J.

Mol. Cell

J. Biol. Chem.

J. Biol. Chem.

Virology

FEBS Lett.

Vet. Microbiol.

Activity of the hepatitis A virus IRES requires association between the cap-binding translation initiation factor (eIF4E) and eIF4G

J. Virol.

Inhibition of U snRNP assembly by a virus-encoded proteinase

Genes Dev.

Differential factor requirement to assemble translation initiation complexes at the alternative start codons of foot-and-mouth disease virus RNA

RNA

Glycyl-tRNA synthetase specifically binds to the poliovirus IRES to activate translation initiation

Nucleic Acids Res.

Translation of polioviral mRNA is inhibited by cleavage of polypyrimidine tract-binding proteins executed by polioviral 3C(pro)

J. Virol.

Structure of the 5′ nontranslated region of the coxsackievirus b3 genome: chemical modification and comparative sequence analysis

J. Virol.

The picornavirus avian encephalomyelitis virus possesses a hepatitis C virus-like internal ribosome entry site element

J. Virol.

Sequence and secondary structure requirements in a highly conserved element for foot-and-mouth disease virus internal ribosome entry site activity and eIF4G binding

J. Gen. Virol.

Structure and dynamics of coxsackievirus B4 2A proteinase, an enyzme involved in the etiology of heart disease

J. Virol.

A nucleo-cytoplasmic SR protein functions in viral IRES-mediated translation initiation

EMBO J.

Dual initiation sites of protein synthesis on foot-and-mouth disease virus RNA are selected following internal entry and scanning of ribosomes in vivo

EMBO J.

Foot-and-mouth disease virus 3C protease induces cleavage of translation initiation factors eIF4A and eIF4G within infected cells

J. Virol.

Requirement of poly(rC) binding protein 2 for translation of poliovirus RNA

J. Virol.

Cleavage of poly(A)-binding protein by poliovirus 3C proteinase inhibits viral internal ribosome entry site-mediated translation

J. Virol.

Unr is required in vivo for efficient initiation of translation from the internal ribosome entry sites of both rhinovirus and poliovirus

J. Virol.

Identification of gemin5 as a novel 7-methylguanosine cap-binding protein

PLoS ONE

The 5′ nontranslated region of hepatitis A virus RNA: secondary structure and elements required for translation in vitro

J. Virol.

Functional analysis of the two alternative translation initiation sites of foot-and-mouth disease virus

J. Virol.

RNA nuclear export is blocked by poliovirus 2A protease and is concomitant with nucleoporin cleavage

J. Cell Sci.

Cellular mRNA decay protein AUF1 negatively regulates enterovirus and human rhinovirus infections

J. Virol.

40S recruitment in the absence of eIF4G/4A by EMCV IRES refines the model for translation initiation on the archetype of Type II IRESs

Nucleic Acids Res.

Hepatitis C virus-related internal ribosome entry sites are found in multiple genera of the family Picornaviridae

J. Gen. Virol.

Functional analyses of RNA structures shared between the internal ribosome entry sites of hepatitis C virus and the picornavirus porcine teschovirus 1 Talfan

J. Virol.

Inhibition of poliovirus-induced cleavage of cellular protein PCBP2 reduces the levels of viral RNA replication