New insights into internal ribosome entry site elements relevant for viral gene expression

Abstract

A distinctive feature of positive-strand RNA viruses is the presence of high-order structural elements at the untranslated regions (UTR) of the genome that are essential for viral RNA replication. The RNA of all members of the family Picornaviridae initiate translation internally, via an internal ribosome entry site (IRES) element present in the 59 UTR. IRES elements consist of cis-acting RNA structures that usually require specific RNA-binding proteins for translational machinery recruitment. This specialized mechanism of translation initiation is shared with other viral RNAs, e.g. from hepatitis C virus and pestivirus, and represents an alternative to the cap-dependent mechanism. In cells infected with many picornaviruses, proteolysis or changes in phosphorylation of key host factors induces shut off of cellular protein synthesis. This event occurs simultaneously with the synthesis of viral gene products since IRES activity is resistant to the modifications of the host factors. Viral gene expression and RNA replication in positive-strand viruses is further stimulated by viral RNA circularization, involving direct RNA-RNA contacts between the 59 and 39 ends as well as RNA-binding protein bridges. In this review, we discuss novel insights into the mechanisms that control picornavirus gene expression and compare them to those operating in other positive-strand RNA viruses.

Picornavirus IRES elements: RNA structure and host protein interactions

“…Briefly, from 5 to 3 direction the 5 UTR comprises a long hairpin (termed S, ranging from 40 nts in kobuvirus, 86 nts in cardiovirus, to 367 nts in aphthovirus). This is followed by a polyC-tract (varying from 50 Cs in cardiovirus to 100-500 in aphthovirus isolates), two to five pseudoknots (Pk) in cardio-, aphtho-, kobu-, parecho-, and hepatovirus, the cis-acting replication element (cre) only in aphthovirus, and finally, the IRES element (see Martinez-Salas et al, 2008 for a review).…”

“…A distinctive feature of picornavirus IRES is their long length, which vary from 280 to 460 nts depending on the genus. According to RNA secondary structure, picornavirus IRES have been classified into different types (designated I, II, III, and HCV-like that, in turn, include subtypes A and B) (Belsham, 2009;Hellen and de Breyne, 2007;Martinez-Salas et al, 2008).…”

Local RNA flexibility perturbation of the IRES element induced by a novel ligand inhibits viral RNA translation

“…The viral genome consists of a positive polarity single-stranded RNA of about 8500 bases, encoding a single open reading frame flanked by a highly structured untranslated region (UTR) at the 5´end of about 1200 nucleotides. 7 Upon entry into the cell, the viral genome is immediately translated into a polyprotein that is processed by virus-encoded proteases. Translation and replication of the viral genome occurs in the cytoplasm of infected cells.…”

“…4 These elements, which were discovered in picornavirus genomic RNAs, 5,6 are in charge of driving translation initiation in various RNA viruses and a subset of cellular mRNAs. 7,8 IRES-driven translation initiation represents an alternative mechanism to start protein synthesis under situations that compromise cap-dependent translation initiation, typically occurring in infected cells. Under normal situations, however, most eukaryotic mRNAs initiate translation by a mechanism that depends on the recognition of the m 7 GpppN residue (termed cap) located at the 5' end of most mRNAs.…”

“…7,8 IRES-driven translation initiation represents an alternative mechanism to start protein synthesis under situations that compromise cap-dependent translation initiation, typically occurring in infected cells. Under normal situations, however, most eukaryotic mRNAs initiate translation by a mechanism that depends on the recognition of the m 7 GpppN residue (termed cap) located at the 5' end of most mRNAs. 9 IRES elements exhibit a wide diversity of nucleotide sequences, RNA secondary structures and trans-acting factors requirements, as illustrated by those present in the genome of picornaviruses and the hepatitis C virus (HCV).…”