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Chapter 9 : Translation and Protein Processing

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Abstract:

This chapter addresses the main features concerning picornavirus gene expression. Picornavirus genomes are tightly packed; the RNA encodes a single poly protein whose translation is governed by the internal ribosome entry site (IRES) element using a cap-independent mechanism that hijacks the translation machinery. Picornavirus IRES activity depends on the coordination of RNA structure and RNA-protein interactions. RNA probing of the entire element revealed long-distance interactions within the 5' untranslated region (UTR) of coxsackievirus B3 (CVB3), thereby providing information on overall IRES structure. Despite the fact that many IRES -acting factors (ITAFs) are promiscuous RNA-binding proteins, IRESs exhibit distinct requirements in terms of functional RNA-protein associations. Ribonucleoprotein complexes assembled on IRESs share various components with the spliceosome, as in the case of SRp20, polypyrimidine tract-binding protein (PTB), or hnRNP A1. Most of the knowledge on factors required for IRES activity comes from in vitro assays. The study of IRES-ribonucleoprotein complexes in living cells has been addressed using reagents that are permeable to the cell membrane and recognize RNA molecules in a structure-dependent manner. Picornaviral genome RNAs encode their proteins in a single, long open reading frame (ORF), translated into a single poly protein. The presence of 3C and 3C-like proteinase domains in a wide range of positive-stranded RNA virus poly proteins argues strongly that this proteolytic domain was acquired at an early stage in the evolution of these viruses.

Citation: Martínez-Salas E, Ryan M. 2010. Translation and Protein Processing, p 140-161. In Ehrenfeld E, Domingo E, Roos R (ed), The Picornaviruses. ASM Press, Washington, DC. doi: 10.1128/9781555816698.ch9
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Figures

Image of Figure 1.
Figure 1.

Primary polyprotein cleavages. (A) The polyprotein organization (boxed areas) is shown for viruses in which the primary polyprotein cleavage between the capsid proteins and replication protein precursors have been shown, or are assumed, to be mediated by the 3C proteinase (3C). Primary cleavages are shown as curved arrows, and regions involved in processing are shown by darker shading. (B) Polyproteins in which the primary cleavage between the capsid proteins and replication protein precursors is mediated by the 2A translational recoding sequence (CHYSEL). All polyproteins here encode an L protein, but only in the case of the aphtho- and erboviruses is L a proteinase (L), which mediates a primary cleavage at its own C terminus. (C) The enteroviruses have been shown to possess a proteolytic form of 2A protein (2A), and the sapeloviruses SV2 and PEV8 are also thought to possess this form of 2A. In all cases a primary cleavage, mediated by 3C, occurs at the 2C/3A site. Designations for the different primary cleavage products generated are shown inside brackets.

Citation: Martínez-Salas E, Ryan M. 2010. Translation and Protein Processing, p 140-161. In Ehrenfeld E, Domingo E, Roos R (ed), The Picornaviruses. ASM Press, Washington, DC. doi: 10.1128/9781555816698.ch9
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Image of Figure 2.
Figure 2.

Secondary polyprotein processing. Secondary processing events mediated by 3C are shown as curved arrows. (A) Enterovirus capsid protein precursors (P1) are processed by the 3CD proteinase (3CD) rather than 3C. The 3D polymerase may be cleaved by 2A to produce 3C′ and 3D′ (vertical arrow). The 1A/1B (VP4/VP2) maturation cleavage occurs concomitantly with the encapsidation of vRNA by an unknown mechanism. (B) In aphthoviruses the capsid protein precursor (P1-2A) may be processed by 3C, but it is processed more efficiently by 3DC. The 2A oligopeptide (18 aa) is trimmed away from 1D by 3C or 3CD. Secondary processing of the P3 precursor is highly complex, as the multiple 3B (VPg) proteins give rise to a series of alternative processing events generating the 3AB and 3CD complex of protein bands seen on SDS-PAGE gels. (C) In viruses with the nonproteolytic forms of L and 2A proteins (typified here by cardioviruses), these proteins are processed by 3C or 3CD. The host cell proteinase cleavage of the hepatovirus 1D/2A site is represented by a dotted, vertical arrow.

Citation: Martínez-Salas E, Ryan M. 2010. Translation and Protein Processing, p 140-161. In Ehrenfeld E, Domingo E, Roos R (ed), The Picornaviruses. ASM Press, Washington, DC. doi: 10.1128/9781555816698.ch9
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Image of Figure 3.
Figure 3.

Proteinase active site residues and the 2A CHYSEL motif. Residues comprising the catalytic triad of the 3C, 2A, and L proteinases are shown (bold, shaded, and with an asterisk, respectively) for representative sequences. For 3C: rhinovirus (HRV2), enterovirus (PV-1), sapelovirus (SV2), hepatovirus (HAV), tremovirus (avian encephalomyelitis virus), aphthovirus (FMDV), cardiovirus (EMCV), senecavirus (Seneca Valley virus), teschovirus (porcine teschovirus 1), cosavirus (human cosa-virus A1), erbovirus (ERBV1), kobuvirus (BK virus), and parechovirus (ECHO-22). For 2A: rhinovirus (HRV2), enterovirus (PV-1), and sapelovirus (SV2). For L: aphthoviruses FMDV, equine rhinitis A virus (ERAV), and bovine rhinitis B virus (BRBV) and the erbovirus equine rhinitis B virus 1. The alignments shown are taken from alignments of all available sequences, together with residues that are completely conserved (bold and shaded) or highly conserved (shaded) among all sequences. Unaligned 2A CHYSEL sequences are shown for aphthovirus (FMDV), erbovirus (ERBV1), teschovirus (PTV-1), cardioviruses (EMCV, TMEV, and Saffold virus), seal picornavirus, human cosavirus A1, Ljungan virus, and duck hepatitis A virus (avihepatovirus). Along with the conserved residues in the C-terminal motif (bold and shaded), 3C cleavage sites (bold) by which the oligopeptide forms of 2A are trimmed from 1D are shown.

Citation: Martínez-Salas E, Ryan M. 2010. Translation and Protein Processing, p 140-161. In Ehrenfeld E, Domingo E, Roos R (ed), The Picornaviruses. ASM Press, Washington, DC. doi: 10.1128/9781555816698.ch9
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Image of Figure 4.
Figure 4.

Sequence diversity of 3C and 2A proteinases. All 2A and 3C sequences were aligned using ClustalX. The phylo-gram was constructed using Dendroscope, and representative members of branches were chosen to illustrate the extent of sequence diversity. 3C sequences are considerably more diverse than those of 2A. Although the sapelovirus 2As appear to be slightly more related to 3C, examination of the alignments shows that relative to 2A, sapelovirus 2A bears three large insertions within the N-terminal region but has high similarity with the C-terminal domain of 2A.

Citation: Martínez-Salas E, Ryan M. 2010. Translation and Protein Processing, p 140-161. In Ehrenfeld E, Domingo E, Roos R (ed), The Picornaviruses. ASM Press, Washington, DC. doi: 10.1128/9781555816698.ch9
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Image of Figure 5.
Figure 5.

Scheme of 2A CHYSEL translational recoding. Peptidyl-tRNA is located in the ribosome A-site (step a). Peptidyl-tRNA is translocated to the P-site, allowing ingress of prolyl-tRNA into the A-site (step b). Interaction of 2A with the ribosome exit tunnel, plus the tight turn, precludes the peptidyl-tRNA ester linkage from nucleophilic attack, as prolyl-tRNA dissociates from the ribosome (step c). eRF1 enters the A-site (step d) and hydrolyzes the ester bond (step e). eRF1 leaves the A-site (promoted by eRF3), and the nascent peptide is released from the ribosome (step f). Prolyl-tRNA (re)enters the A-site (step g) and is translocated to the P-site by eEF2 (step h). The next amino-acyl-tRNA enters the A-site, and sequences downstream of 2A are translated (step i). An alternative outcome is that the ribosome subunits may dissociate and translation is terminated. Our model predicts this could occur at any of the stages indicated in steps f to i.

Citation: Martínez-Salas E, Ryan M. 2010. Translation and Protein Processing, p 140-161. In Ehrenfeld E, Domingo E, Roos R (ed), The Picornaviruses. ASM Press, Washington, DC. doi: 10.1128/9781555816698.ch9
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Tables

Generic image for table
Table 1.

RNA-binding proteins that interact with picornavirus IRESs

Citation: Martínez-Salas E, Ryan M. 2010. Translation and Protein Processing, p 140-161. In Ehrenfeld E, Domingo E, Roos R (ed), The Picornaviruses. ASM Press, Washington, DC. doi: 10.1128/9781555816698.ch9

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