One for all? A viral protein supplants the mRNA cap‐binding complex

Modulation of the host cell’s translational machinery is a crucial part of viral infection strategies. Well-characterised mechanisms that aid viruses in manipulating translational activity include, for example, internal ribosomal entry sites, which allow viral RNA translation in the absence of some or many of the canonical host translation factors. New research shows that the nucleocapsid protein from a species of Hantavirus can replace several host cell translation factors in in vitro translation reactions, suggesting that hantaviruses may have evolved a novel strategy for modulating host cell translation in the form of a multifunctional translation factor. Cellular translation is an intricate and complicated process. Ribosomes need to bind to mRNAs with the correct frequency, they need to locate the correct start codon, then decode the mRNA using the right balance of speed and accuracy, and stop translation and release the nascent polypeptide when they encounter a termination codon. During normal cellular translation, the interplay of all of these processes is regulated by a complex repertoire of translation factors. Translation of the majority of eukaryotic cellular mRNAs is dependent on the presence of a specific modification at their 50-end, the mG cap structure. Cap-dependent translation relies on a specific subset of translation factors termed the cap-binding complex (reviewed in Kapp and Lorsch, 2004; von der Haar et al, 2004; Sonenberg and Hinnebusch, 2007). The eIF4E subunit of this complex binds to the cap structure, and tethers another subunit, eIF4G, to the mRNA 50-end. eIF4G has at least two specific roles in cap-dependent translation, namely the recruitment of the RNA helicase activity provided by eIF4A, which removes secondary structure from the site of attachment of the small ribosomal subunit; and the recruitment of the small ribosomal subunit itself, which occurs through contacts between eIF4G and other, small ribosomal subunit-associated translation factors. During viral infection, the expression of viral genes is also achieved through the translational machinery of the host cell. Shut down of normal cellular translation is consequently one of the first cellular defence mechanisms against viral infection. Viruses have evolved many different tools that enable them to maintain translation of their own RNA despite attempts of the cell to shut down translation, and despite the competition of cellular mRNAs for access to the translational machinery. Although these tools differ between different viruses, most of them are built on a common principle: they involve the replacement of cellular translation factors with purpose-built viral factors that are efficient translational activators, and that are also usually highly selective for the viral RNA (Figure 1). The currently best understood of these tools are the viral internal ribosomal entry sites (IRESs), in particular those from the Picornaviridae family (for a recent review, see e.g. Martinez-Salas et al, 2008). IRESs are secondary RNA structures that act in cis, mediating recruitment of ribosomal subunits by virtue of their three-dimensional structure. The actual mechanism of recruitment differs greatly between different viral families, and may involve direct contacts between the IRES and ribosome without involvement of any initiation factors as in the case of the Dicistroviridae intergenic IRESs, or may be mediated by subsets of translation factors that are also involved in ribosome recruitment during normal cap-dependent translation. Other viruses employ less well-