Viruses utilize a number of translational control mechanisms to regulate the relative expression levels of viral proteins on polycistronic mRNAs. One such mechanism, that of termination-dependent reinitiation, has been described in a number of both negative- and positive-strand RNA viruses. Dicistronic RNAs which exhibit termination–reinitiation typically have a start codon of the 3′-ORF (open reading frame) proximal to the stop codon of the upstream ORF. For example, the segment 7 RNA of influenza B is dicistronic, and the stop codon of the M1 ORF and the start codon of the BM2 ORF overlap in the pentanucleotide UAAUG (the stop codon of M1 is shown in bold and the start codon of BM2 is underlined). Recent evidence has highlighted the potential importance of mRNA–rRNA interactions in reinitiation on caliciviral and influenza B viral RNAs, probably used to tether 40S ribosomal subunits to the RNA after termination in time for initiation factors to be recruited to the AUG of the downstream ORF. The present review summarizes how such interactions regulate reinitiation in an array of RNA viruses, and discusses what is known about reinitiation in viruses that do not rely on apparent mRNA–rRNA interactions.

Reinitiation of translation

Reinitiation of translation on viral mRNAs (other than that observed for plant pararetroviruses, discussed below) represents a separate mechanism from that of short ORF (open reading frame)-directed reinitiation (reviewed in [1]) in that the first cistron has no apparent restriction on its size and it encodes a functional protein, yet no viral encoded transactivator is needed. There are common features between all of the known examples of termination–reinitiation except for the plant pararetroviruses. (i) The termination codon must be placed within close proximity of the start site of translation of the downstream cistron (<40 nt). Any increase in this distance reduces reinitiation markedly [29], perhaps due to the ribosome being unable to locate the start codon if it is too far away, or alternatively due to the terminating ribosome being too distant from upstream sequences that tether the 40S subunit ([6,9], and discussed below). The stop and start codons of the two cistrons typically overlap, with the second ORF in a different reading frame from that of the first, ruling out stop codon suppression in the synthesis of the downstream product. Importantly, no fusion of the first and second ORFs is expressed, ruling out programmed ribosomal frameshifting in the synthesis of the downstream ORF. (ii) Termination at the first ORF stop codon is an absolute requirement for reinitiation on the downstream ORF, distinguishing reinitiation from intergenic IRES (internal ribosome entry site)-mediated mechanisms of downstream start codon accession [2,3,5,7,913]. Interestingly, there is very little conservation of the region where the uORF (upstream ORF) and the downstream ORF overlap (see Figure 1, shown in cyan) even within virus families.

Sequence alignment of caliciviral termination–reinitiation signals and 5′-flanking regions

Figure 1
Sequence alignment of caliciviral termination–reinitiation signals and 5′-flanking regions

Caliciviral termination–reinitiation signals and 5′-flanking regions are compared. The termination–reinitiation signal of influenza BM2 is also shown, as is a putative signal in the cellular gene glutamic acid decarboxylase. Confirmed and potential motif 1 sequences are highlighted in pink and the stop–start window is in blue. Potential base-pairing interactions (motif 2 and motif 2*) flanking motif 1 are indicated in grey (or underlined in the case of the glutamic acid decarboxylase gene). Within the murine noroviruses, with reference to EU004666, base changes are highlighted in green. Reprinted from [7] with permission.

Figure 1
Sequence alignment of caliciviral termination–reinitiation signals and 5′-flanking regions

Caliciviral termination–reinitiation signals and 5′-flanking regions are compared. The termination–reinitiation signal of influenza BM2 is also shown, as is a putative signal in the cellular gene glutamic acid decarboxylase. Confirmed and potential motif 1 sequences are highlighted in pink and the stop–start window is in blue. Potential base-pairing interactions (motif 2 and motif 2*) flanking motif 1 are indicated in grey (or underlined in the case of the glutamic acid decarboxylase gene). Within the murine noroviruses, with reference to EU004666, base changes are highlighted in green. Reprinted from [7] with permission.

To date, termination–reinitiation has been shown to occur experimentally in the positive-strand RNA viruses of the Caliciviridae family: FCV (feline calicivirus) [4,9,11], RHDV (rabbit haemorrhagic disease virus) [6,12], JV (bovine norovirus Jena) [5] and MNV (murine norovirus) [7]. It has also been shown to occur in the negative-stranded Orthomyxovirus influenza B [8,10,14] and in the Pneumovirinae subfamily in RSV (respiratory syncytial virus) [2,15,16], APV (avian pneumovirus) and PVM (pneumovirus of mice) [16]. Finally, reinitiation has been shown to be utilized in the fungal dsRNA (double-stranded RNA) virus family, in the Hypovirus CHV1 (Cryphonectria hypovirus 1) [3].

TURBS (termination upstream ribosome-binding site)-dependent mechanisms of reinitiation: caliciviruses and orthomyxoviruses

Caliciviruses

Caliciviral termination–reinitiation is the most widely studied of all of the viral reinitiation events. The caliciviruses produce 3′ co-terminal subgenomic RNAs, all of which are dicistronic. VP (viral protein) 2 of FCV and MNV, and VP10 of RHDV have all been shown to be synthesized by termination–reinitiation-dependent mechanisms [4,6,7,11,12]. JV also has a similar genome organization and it has been proposed that ORF3 can be accessed through reinitiation, although this has not been proved experimentally [5]. However, there is evidence that ORF2 (normally the 5′-most ORF of the subgenomic RNA) can be accessed both from the subgenomic RNA, and also by reinitiation following ORF1 translation on the genomic RNA [5]. Given the similar genome organization of all of the caliciviruses (Figure 1), it is likely that all ORF3 homologues on the subgenomic RNA are accessed by termination–reinitiation. It may also be that the ORF2 equivalents among the caliciviruses can be accessed both in a cap-dependent manner, and also by reinitiation following translation of ORF1, although this has yet to be demonstrated experimentally.

To date, all of the published cases of caliciviral termination–reinitiation have been shown to be dependent on sequences immediately 5′ of the reinitiation overlap region (Figure 1). Deletion analysis suggests that the lengths of these sequences is variable, with 84 nt required for RHDV VP10 synthesis [12], 69–84 nt for FCV VP2 expression [9,11] and only 40–43 nt for reinitiation on MNV VP2 [7]. Conversely, there is no dependence on sequences downstream of the reinitiation window, as reporter genes can replace the downstream ORF with no effect on reinitiation [7,9,12]. This is distinct from reinitiation in retrotransposons (which otherwise is apparently similar to the viral cases of reinitiation described here, see [17]), which require complex downstream secondary structures for reinitiation. Unlike in certain cases of eukaryotic termination–reinitiation {for example, that of the AdoMetDC (S-adenosylmethionine decarboxylase) mRNA [18]}, the protein encoded by the upstream ORF has no effect on the rate of reinitiation in FCV or RHDV as the protein can be altered by introduction of a frameshift mutation or almost complete replacement with a reporter ORF without detrimental effect [7,12], suggesting that the required element upstream of the overlap region is based on the mRNA sequence itself.

So how does the primary sequence upstream of the ORF1/2 (of JV) and ORF2/3 (of FCV, RHDV and MNV) promote reinitiation? Analysis of deletion mutants of RHDV, FCV and MNV reporter mRNAs reveals that the minimal sequence requirement for reinitiation includes a region of viral RNA complementary to the apical loop of helix 26 of 18S rRNA [4,6,7,11]. Similar sequences are found ~30–60 nt upstream of all of the caliciviral ORF3 equivalents [7], and also upstream of the ORF1/2 boundary of genogroup II, III and IV noroviruses (Lordsdale, JV and Saint Cloud viruses respectively [5], Figure 1). Although it has not been proved directly, it has been suggested that base pairing may occur between the viral RNA and the 18S rRNA. This raises the possibility that this interaction may act to tether the 40S subunit to the RNA after termination, allowing time for recruitment of initiation factors and subsequent reinitiation on the downstream ORF (see Figure 2 for a model of how TURBS-regulated reinitiation is thought to occur). As such, the upstream sequence has been named the termination upstream ribosome-binding site or TURBS [6,11]. The TURBS is made up of three core motifs: motif 1 (the 18S rRNA complementary region), motif 2 and motif 2* (thought to be involved in forming RNA secondary structures, Figure 1) [4,6,11]. So what evidence is there for an 18S rRNA–viral mRNA interaction? First, a number of mutations that would be expected to abrogate base pairing between helix 26 and the viral RNA effectively block reinitiation in vivo in FCV and RHDV [4,6,11], and in vitro in reporters encoding the ORF2/3 reinitiation windows of MNV [7]. The same is also true in reporters encoding the ORF1/2 overlap region of JV [5]. Mutational analysis of every base of FCV motif 1 reveals that the highly conserved UGGGA sequence is key in reinitiation and forms the core of motif 1 [4]. Recently, Luttermann and Meyers [4] performed an analysis of FCV reinitiation in yeast, whereby both the viral RNA and the 18S rRNA were mutated such that an interaction could be proved more rigorously. Abolition of base pairing with the yeast 18S rRNA abrogated ORF3–GFP (green fluorescent protein)–myc expression almost completely. Importantly, compensatory mutations of the 18S rRNA such that base pairing could be re-established effectively restored reinitiation on the ORF3 AUG codon to wild-type levels [4]. Taken together, these data provide good evidence that 18S rRNA interactions with motif 1 are likely to be important in reinitiation in the caliciviruses.

A model of TURBS-dependent termination–reinitiation

Figure 2
A model of TURBS-dependent termination–reinitiation

(a) The 80S ribosome translates the uORF as normal. (b) As the ribosome approaches the overlap region, the stretch of RNA containing motif 1 is translated and may be remodelled. During termination, the secondary structure (indicated with an asterisk) including motif 1 is located in the exit channel of the ribosome. This translational remodelling may promote the binding of eIF3, which has been shown to promote reinitiation. (c) The secondary structure presents motif 1 of the TURBS to the solvent-accessible helix 26 of the 18S rRNA. This interaction may be stabilized by the presence of eIF3, also known to contact the 18S rRNA. These interactions act to tether the ribosome to the viral RNA, preventing its dissociation, allowing time for the recruitment of initiation factors and subsequent reinitiation on the downstream ORF.

Figure 2
A model of TURBS-dependent termination–reinitiation

(a) The 80S ribosome translates the uORF as normal. (b) As the ribosome approaches the overlap region, the stretch of RNA containing motif 1 is translated and may be remodelled. During termination, the secondary structure (indicated with an asterisk) including motif 1 is located in the exit channel of the ribosome. This translational remodelling may promote the binding of eIF3, which has been shown to promote reinitiation. (c) The secondary structure presents motif 1 of the TURBS to the solvent-accessible helix 26 of the 18S rRNA. This interaction may be stabilized by the presence of eIF3, also known to contact the 18S rRNA. These interactions act to tether the ribosome to the viral RNA, preventing its dissociation, allowing time for the recruitment of initiation factors and subsequent reinitiation on the downstream ORF.

Given that the primary sequence requirement for reinitiation in caliciviruses is larger than that of motif 1 alone, it is tempting to speculate that some kind of RNA secondary structure may be involved in reinitiation. Separate studies by Poyry et al. [9] and Luttermann and Meyers [4] have proposed similar structures for the TURBS of FCV (Figure 3a). The MNV TURBS has also been shown to have some degree of secondary structure (Figure 3b), and in all caliciviral cases, motif 2 base-pairs with motif 2* to form the stem [7]. The structures of FCV and MNV are distinct (which explains why motif 2 is not highly conserved, Figure 1 and Figure 3), yet both act to present motif 1 within predominantly single-stranded regions (or weakly base-paired regions, Figure 3a and 3b), consistent with a role for mRNA–18S rRNA interactions in the reinitiation process [4,7,9]. Interestingly, the MNV structural analysis posits two structures [7] (Figure 3b), one of which is unable to form when the ribosome is placed at the termination site (and in which motif 1 is sequestered in a base-paired region, Figure 3b, left-hand panel) and one which would form just 5′ of the terminating ribosome (where motif 1 is only weakly base-paired, Figure 3b, right-hand panel). This finding may suggest why translation through the uORF is required for downstream ORF expression, in that the ribosome may translationally remodel the RNA from a conformation where motif 1 is unavailable to a structure where motif 1 is more able to base-pair with the 18S rRNA. One caveat of the structural data lies in the fact that mutations of the TURBS that disrupt the top stem of the FCV secondary structure effectively abrogate reinitiation [4], yet deletion of most of the sequence between motif 1 and motif 2 (which would include most of the structure) has little effect on the levels of VP2 in cells [11]. Therefore more work is required to determine the role of TURBS secondary structure in reinitiation.

Secondary structures of caliciviral and influenza B TURBS

Figure 3
Secondary structures of caliciviral and influenza B TURBS

Stretches of bases shown in bold indicate motif 1, bases shown in bold italic show the termination–reinitiation overlaps. The black solid line indicates the 5′-most end of the minimal required region for reinitiation to occur. The broken line shows the likely position of the 5′-edge of a ribosome that is located at the termination codon. (a) The FCV TURBS. Note that no alternative structures have been posited for this reinitiation signal. Structure based on [4]. (b) The MNV TURBS structures. Once the uORF has been translated, structure 1 would be unable to form and it is thought that the RNA is translationally remodelled into structure 2. Structure based on [7]. (c) Structure of the influenza B TURBS. Similarly to the MNV structures, it is thought that structure 1 may be remodelled into structure 2 by translation of the ribosome through the uORF and termination at the VP1 stop codon. Structure based on [8].

Figure 3
Secondary structures of caliciviral and influenza B TURBS

Stretches of bases shown in bold indicate motif 1, bases shown in bold italic show the termination–reinitiation overlaps. The black solid line indicates the 5′-most end of the minimal required region for reinitiation to occur. The broken line shows the likely position of the 5′-edge of a ribosome that is located at the termination codon. (a) The FCV TURBS. Note that no alternative structures have been posited for this reinitiation signal. Structure based on [4]. (b) The MNV TURBS structures. Once the uORF has been translated, structure 1 would be unable to form and it is thought that the RNA is translationally remodelled into structure 2. Structure based on [7]. (c) Structure of the influenza B TURBS. Similarly to the MNV structures, it is thought that structure 1 may be remodelled into structure 2 by translation of the ribosome through the uORF and termination at the VP1 stop codon. Structure based on [8].

Tethering of the 40S subunit to the mRNA is not the only function that has been attributed to the TURBS. Cross-linking analysis of the FCV TURBS has also demonstrated that it is able to bind the multisubunit eIF (eukaryotic initiation factor) 3 [9]. eIF3 plays a crucial role in translation initiation by virtue of the contacts it makes with eIF1, eIF2, eIF4G and eIF5 and also with the 40S ribosomal subunit {in yeast, although many of these interactions have also been demonstrated in higher eukaryotes (for a review, see [19])}. eIF3 has also been shown to play a role in dissociation of the 40S and 60S ribosomal subunits during termination, a process which is enhanced by eIF1/1A and the loosely associated eIF3j [20]. Importantly, eIF3 is able to stimulate reinitiation on FCV mRNAs, and it has therefore been suggested that it may bind the TURBS, increasing the rate of ribosome recycling, giving the tethered 40S subunit more time to acquire initiation factors and reinitiate before the 40S subunit dissociates from the RNA [9]. However, recent data suggest that eIF3-mediated ribosome recycling only occurs over a narrow range of Mg2+ concentrations, with the ATP-binding cassette protein ABCE1 performing the same role over a broader range [21]. These data may rule out a requirement for eIF3 in increasing the rate of FCV VP60 termination. Bound eIF3 may also play a further role in recruitment of initiation factors for reinitiation (as these are presumably lost during elongation of the long uORF [22,23]), by virtue of its interactions with components of the initiation complex. It is also possible that eIF3 could aid in ribosomal subunit tethering, since eIF3 has been shown to bind 40S subunits directly [2426]. Interestingly, mutation of the UGGGA core of motif 1 also abrogates eIF3 binding, which may suggest that motif 1 plays a dual role in 40S tethering and eIF3 recruitment [9].

Orthomyxovirus: influenza B

Influenza B is a segmented negative-stranded RNA virus of which segment 7 encodes both the M1 and BM2 proteins. The BM2 ORF is situated at the 3′-end of the segment 7 RNA and its start codon overlaps with the termination codon of M1 in the UAAUG (the stop codon of M1 is shown in bold and the start codon of BM2 is underlined) pentanucleotide [8,10,14] (Figure 1). The BM2 ORF is accessed by termination–reinitiation, and is regulated in a highly similar manner to the caliciviral mechanisms described above [8]. Reinitiation on the BM2 ORF is dependent on ~45 nt directly upstream of the UAAUG overlap [8,14], and this region contains the motif 1 UGGGA core [8] (Figure 1). Mutational analysis of motif 1 reveals that mRNA–18S rRNA base pairing is likely to also be involved in reinitiation on the BM2 ORF [8].

RNA secondary structure has been suggested to play a role in the presentation of motif 1 to the 18S rRNA and, similarly to the situation seen in MNV, two putative structures of the influenza B TURBS are suggested on the basis of secondary-structure predictions and enzymatic and chemical probing of the RNA [8] (Figure 3c). Also similar is the fact that one of the structures has motif 1 sequestered in a base-paired region of the mRNA, but termination at the M1 stop codon prevents this structure from forming, instead allowing a small stem to form directly 5′ of the 40S subunit in which motif 1 is freely presented on the apical loop [8] (Figure 3c). These data provide further evidence that translational remodelling of the RNA may ‘free up’ motif 1 such that an interaction with the 18S rRNA can occur, although the role of secondary structure in reinitiation on the BM2 ORF remains to be demonstrated.

Also in common with caliciviral termination–reinitiation [6,11], synthesis of BM2 can occur in the absence of a canonical start codon, and can even occur (at about one-quarter of wild-type efficiency) when the BM2 start codon is mutated to UCG [8]. Furthermore, mutation of the nucleotides surrounding the start codon suggests that context effects (i.e. the Kozak consensus of the start codon) have little effect on reinitiation [8]. These data suggest that placement of the ribosome at the reinitiation site circumvents the normal requirements for start codon selection, and may rule out eIF1 and eIF1A in the reinitiation process (since they are known to be required for canonical start site recognition [27]).

Termination–reinitiation in the pneumo- and metapneumo-viruses

Termination–reinitiation has also been shown to allow the synthesis of M2–2 of RSV, APV and PVM, although little is known about the mechanism [2,15,16]. As demonstrated for all other known reinitiation events, sequences upstream of the overlap region are required for synthesis of M2–2 [15,16]. Again, the restart site must be in close proximity to the site of termination, although RSV has been shown to be able to reinitiate on any one of three in-frame M2–2 initiation codons [2]. However, the sequence requirement for reinitiation is much larger than that observed for TURBS-dependent reinitiation events (~250 nt compared with ~40–85 nt for most of the caliciviruses [15]). Furthermore, this required region contains no obvious motif 1 homologue. These data may suggest that termination–reinitiation in the pneumoviruses may occur by a different mechanism from that of the caliciviruses. As yet, the only clues as to how reinitiation is achieved in such viruses is that the region upstream of the M2–2 reinitiation site contains a large secondary structure which is required for efficient M2–2 synthesis [15]. Furthermore, placing this structure upstream of the M2/M2–2 overlap of APV (which reinitiates very poorly) promotes efficient termination–reinitiation [16]. However, how this structure acts is yet to be determined.

Termination–reinitiation in the hypoviruses

CHV1 is associated with the picorna-like superfamily and infects the chestnut blight fungus attenuating its virulence. The genomic RNA consists of two open reading frames A and B, separated by the pentanucleotide UAAUG [3]. No subgenomic RNA for ORF B has been discovered, and ORF B has been demonstrated to be accessed by termination–reinitiation at a frequency of 2.5–4.4% [3]. Reinitiation in CHV1 is slightly inhibited by separation of the stop and start codons by just one nucleotide, although there is little effect of increasing the distance between them further than this (up to 10 nt; how increasing the distance more than this affects reinitiation is not known). However, unlike other studies of termination–reinitiation, in the CHV1 study, the start codon was moved downstream of the stop codon (in all other cases, the stop codon was moved downstream of the start codon). Work on caliciviral and influenza B reinitiation signals indicates that the distance between the stop and start codons may not be the limiting factor in reinitiation efficiency, but rather the distance of the terminating ribosome from the TURBS (which could affect the ability of the TURBS to tether the 40S subunit, [9] and M.L. Powell, K.E. Leigh, T.A.A. Pöyry, R.J. Jackson, T.D.K. Brown and I. Brierly, unpublished work). Although no TURBS has been identified in CHV1, there is dependence on the sequence upstream of the UAAUG, which does have some complementarity with the 18S rRNA [3]. These data may indicate why there is little additional effect of increasing the distance between the stop codon of ORF A and the start codon of ORF B from 1 nt to 10 nt, as the ribosome terminates in the wild-type position relative to the upstream sequence. It is conceivable that there may then be some degree of flexibility in where the ribosome reinitiates. It could also be that both the actual distance between the stop and start codons as well as the distance of where the ribosome terminates relative to critical upstream sequences are important in the reinitiation process. Interestingly (and unlike the caliciviruses), the protein coded for by the upstream sequence (p40) does have an effect on reinitiation levels [3], and, in this respect, it is similar to reinitiation on the AdoMetDC RNA [18]. Whether there is a role for 18S rRNA–mRNA interactions in reinitiation in CHV1 remains to be seen, but, at present, CHV1 seems to represent a novel mechanism for RNA virus termination–reinitiation.

Reinitiation regulated by transactivating proteins: plant pararetroviruses

In the CaMV (cauliflower mosaic virus) 35S RNA, the 5′-most ORF, ORF VII, is accessed by translation through a short ORF in the 5′-UTR (untranslated region). Following termination, the reinitiation-competent 40S subunit shunts past a large stem–loop structure, resumes scanning and re-initiates on the ORF VII AUG, in a manner dependent on TAV (transactivator protein) (for review, see [28]). Interestingly, TAV is also able to support reinitiation between consecutive long coding ORFs on the 35S RNA [2931], even when the downstream AUG is placed some distance from the upstream termination codon [30]. This mechanism is apparently conserved throughout polycistronic RNAs in other plant pararetroviruses, also occurring in FMV (figwort mosaic virus) [32] and PCSV (peanut chlorotic streak virus) [33]. It is thought that, through interactions with a host-encoded transactivator, RISP (reinitiation-supporting protein), TAV is able to retain eIF3 during elongation and recruit the 60S subunit after termination, thus allowing repeated reinitiation events to occur [34].

Conclusions

In summary, a growing number of viruses have been shown to use termination-dependent reinitiation for the expression of downstream ORFs. The mechanisms employed appear to be distinct from the reinitiation that is regulated by short uORFs. Within viral termination–reinitiation systems, many seem to rely on tethering of the ribosome to the mRNA. It will be interesting to see whether more viral or cellular RNAs are found to utilize similar mRNA–ribosome or mRNA–protein–ribosome interactions in the regulated synthesis of their proteins.

Post-Transcriptional Control: mRNA Translation, Localization and Turnover: A Biochemical Society Focused Meeting held at University of Edinburgh, U.K., 8–10 June 2010. Organized and Edited by Matthew Brook (Edinburgh, U.K.), Mark Coldwell (Southampton, U.K.), Simon Morley (Sussex, U.K.) and Nicola Gray (Edinburgh, U.K.).

Abbreviations

     
  • AdoMetDC

    S-adenosylmethionine decarboxylase

  •  
  • APV

    avian pneumovirus

  •  
  • CHV1

    Cryphonectria hypovirus 1

  •  
  • eIF

    eukaryotic initiation factor

  •  
  • FCV

    feline calicivirus

  •  
  • JV

    bovine norovirus Jena

  •  
  • MNV

    murine norovirus

  •  
  • ORF

    open reading frame

  •  
  • PVM

    pneumovirus of mice

  •  
  • RHDV

    rabbit haemorrhagic disease virus

  •  
  • RSV

    respiratory syncytial virus

  •  
  • TAV

    transactivator protein

  •  
  • TURBS

    termination upstream ribosome-binding site

  •  
  • uORF

    upstream ORF

  •  
  • VP

    virus protein

Many thanks to Dr Ian Brierley for the kind provision of Figure 1.

Funding

Our work on termination–reinitiation is supported by a Biotechnology and Biological Sciences Research Council grant to my colleagues Ian Brierley and T. David K. Brown.

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