Picornavirus IRES elements: RNA structure and host protein interactions
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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