3′ Cap-independent translation enhancers of positive-strand RNA plant viruses
Highlights
► Plant viruses utilize unique mechanisms to hijack the host translational machinery. ► 3′CITEs are a class of RNA element that performs this function in Tombusviridae. ► 3′CITEs operate by binding to translation initiation factors or ribosomal subunits. ► Major advances in the field as well as future prospects are discussed herein.
Introduction
To be translated efficiently, most eukaryotic mRNAs contain a 5′-m7GpppN cap structure and a 3′-poly(A) tail. The cap is bound by eukaryotic translation initiation factor 4E (eIF4E) via contacts that include stacking interactions between the 7-methyl guanine of the cap and two tryptophan residues in the eIF4E cap-binding pocket [1, 2]. eIF4E also interacts with eIF4G, forming the eIF4F complex [3]. In plants, the purified eIF4F complex does not include eIF4A [4], whereas this helicase does copurify with the complex isolated from mammals [5]. In both plants and animals, eIF4A is thought to aid in unwinding of the mRNA leader sequence during ribosome scanning. eIF4G acts as a scaffolding protein by binding other initiation factors including eIF3, which recruits the 43S subunit of the ribosome [4], as well as the poly(A)-binding protein (PABP), which binds simultaneously to the poly(A) tail [6]. The 5′cap-eIF4F-PABP-poly(A) tail interaction circularizes the mRNA and enhances translation by stabilizing the interaction between eIF4F and the cap [7].
The RNA genomes of many positive-strand (messenger-sensed) RNA plant viruses are neither 5′-capped nor 3′-polyadenylated and, thus, must employ alternative translation mechanisms to effectively compete for host ribosomes [8]. For some RNA viruses, including members of the Tombusviridae and Luteoviridae families (Table 1), this involves RNA elements in their viral genomes within or near the 3′-untranslated region (3′UTR). These RNA structures, termed 3′ cap-independent translational enhancers (3′CITEs), are essential for efficient translation of these RNA genomes [9]. Different 3′CITEs possess distinctive properties; however, they appear to share some general mechanistic principles that include: first, recruitment of components of the translation machinery via 3′CITE binding, second, communication of the 3′CITE with the viral 5′UTR and third, positioning of the ribosomal subunits at the 5′-end of the viral genome. Collectively, these 3′CITE-mediated events facilitate efficient initiation of translation and, as described herein, recent studies have begun to shed light on the mechanisms by which these RNA elements operate.
Section snippets
Structural classes of 3′CITE
The 3′CITEs identified in uncapped, nonpolyadenylated RNA viruses to date have been grouped into six major classes based on sequence and secondary structure (reviewed in [9]) (Table 1). The first 3′CITE was discovered in satellite Tobacco necrosis virus (sTNV) and was called the translation enhancer domain (TED) [10]. The sTNV TED consists of a 93 nt long sequence that is predicted to form an extended stem-loop (SL) structure (Table 1). In contrast, the 3′CITE in the luteovirus Barley yellow
3′CITE recruitment of translational machinery
Shortly after their discovery, it was proposed that 3′CITEs might function by recruiting translation-related factors to the viral RNA [30, 31]. Of the interactions reported so far, most 3′CITEs bind to the initiation factor complex eIF4F [19••, 27•, 32, 33] (Table 1), consistent with their function as a 5′-cap replacement. In fact, the PTE of PEMV may represent a true 5′-cap mimic, as it binds eIF4E with high affinity (Kd ≈ 58 nm) [16•] and is proposed to do so via the highly flexible guanine
Mechanisms of translational enhancement
Translation is initiated at the 5′-end of viral genomes, thus the distal location of the 3′CITEs that recruit the translational machinery seems counterintuitive. Indeed, this configuration suggests that there must be some form of 5′–3′ communication to facilitate efficient translation at the 5′-end. For most 3′CITEs, this appears to be achieved through formation of an intramolecular RNA–RNA interaction, where sequence in the 3′CITE base pairs with complementary sequence in the 5′UTR of the
Perspectives and future directions
Recent studies have begun to reveal detailed mechanistic insights into how plant RNA virus 3′CITEs enhance translation initiation of 5′-proximal viral genes over long distances. Despite the progress made to date, many questions related to 3′CITE structure, function and evolution remain. Structurally, high-resolution models exist for only two classes of 3′CITE, the PTE and TSS [19••, 21••], thus additional effort is required to solve the higher-order structures of the remaining known classes of
Plant versus animal cap-independent translation
Like their plant virus counterparts, animal plus-strand RNA viruses that lack a 5′cap also employ unconventional strategies to recruit host ribosomes. Currently, no 3′CITEs have been identified in uncapped animal viruses. Instead, these viruses typically contain internal ribosome entry sites (IRESes) in their 5′UTRs [43]. Animal virus IRESes, which are described in the companion article by Reineke and Lloyd [44], provide an interesting contrast to 3′CITEs. An obvious difference between the two
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We thank Allen Miller and members of our laboratory for reviewing the manuscript and providing useful comments. BLN is supported by an NSERC Canada Graduate Scholarship and the research in our laboratory is supported by grants from NSERC, CFI and CRC to KAW. We apologize to those researchers whose works were not presented due to page restrictions.
References (45)
- et al.
Cocrystal structure of the messenger RNA 5′ cap-binding protein (eIF4E) bound to 7-methyl-GDP
Cell
(1997) - et al.
Functional diversity of the eukaryotic translation initiation factors belonging to eIF4 families
Mech Dev
(2005) A tale of two termini: a functional interaction between the termini of an mRNA is a prerequisite for efficient translation initiation
Gene
(1998)- et al.
Translational control in positive strand RNA plant viruses
Virology
(2006) - et al.
Base-pairing between untranslated regions facilitates translation of uncapped, nonpolyadenylated viral RNA
Mol Cell
(2001) - et al.
Rose spring dwarf-associated virus has RNA structural and gene-expression features like those of Barley yellow dwarf virus
Virology
(2008) - et al.
Structural plasticity of Barley yellow dwarf virus-like cap-independent translation elements in four genera of plant viral RNAs
Virology
(2010) - et al.
Structure of a viral cap-independent translation element that functions via high affinity binding to the eIF4E subunit of eIF4F
J Biol Chem
(2009) - et al.
Long-distance kissing loop interactions between a 3′ proximal Y-shaped structure and apical loops of 5′ hairpins enhance translation of Saguaro cactus virus
Virology
(2011) - et al.
The 3′ proximal translational enhancer of Turnip crinkle virus binds to 60S ribosomal subunits
RNA
(2008)