Abstract
Initiation of eukaryotic mRNA translation may proceed via several different routes, each requiring a different subset of factors and relying on different and specific interactions between the mRNA and the ribosome. Two modes predominate: (i) so-called cap-dependent initiation, which requires all canonical initiation factors and is responsible for about 95–97% of all initiation events in eukaryotic cells; and (ii) cap-independent internal initiation, which requires a reduced subset of initiation factors and accounts for up to 5% of the remaining initiation events. Internal initiation relies on the presence of so-called internal ribosome entry site (IRES) elements in the 5′ UTRs of some viral and cellular mRNAs. These elements (often possessing complex secondary and tertiary structures) promote efficient interaction of the mRNA with the 40S ribosome and allow for internal ribosome entry. Internal initiation of translation of specific mRNAs may contribute to development of severe disease and pathological states, such as hepatitis C and cancer. Therefore, this cellular mechanism represents an attractive target for pharmacological modulation. The purpose of this review is to provide insight into current strategies used to target viral and cellular IRESs and discuss the physiological consequences (and potential therapeutic implications) of abrogation/modulation of IRES-mediated translation.
Highlights
Eukaryotic cells utilize several modes to initiate translation of their messenger RNAs
Canonical cap-dependent initiation involves several major steps [1, 2]. It starts with activation of the messenger RNAs (mRNAs), which exits the nucleus as an mRNP complex [8], and needs to be mobilized for translation [1, 2, 5,6,7,8], and ends with assembly of the elongation-competent 80S complex at the AUG codon. mRNP activation is initiated by binding of eukaryotic initiation factor 4F, which consists of three proteins: (i) eIF4E, the cap-binding protein; (ii) eIF4G, the scaffolding protein that serves as a bridge between the mRNA and the 40S ribosome via interaction with 40S-bound eIF3; and (iii) eIF4A, the ATP-dependent helicase. mRNA activation leads to ATP-dependent removal of secondary structures and proteins from the 5′ end of the mRNA [1, 2]
Regardless of the exact molecular mechanism(s) involved, it is clear that initiation of translation of eukaryotic mRNAs may proceed via several different routes, each requiring a different subset of factors and relying on different specific interactions between the mRNA and the ribosome [1, 5,6,7, 30]
Summary
Eukaryotic cells utilize several modes to initiate translation of their messenger RNAs (mRNAs). Regardless of the exact molecular mechanism(s) involved, it is clear that initiation of translation of eukaryotic mRNAs may proceed via several different (non-cap-dependent) routes, each requiring a different subset of factors and relying on different specific interactions between the mRNA (harboring specific internal ribosome “landing” regions like IRESs) and the ribosome [1, 5,6,7, 30] This suggests that translation driven by IRES elements such as viral IRESs that differ in the complexity of their secondary structures or utilize different subsets of initiation factors and ITAFs in comparison with cellular mRNAs might represent attractive targets for pharmacological modulation. We review current strategies used to target viral and cellular IRESs and discuss the physiological consequences (and potential therapeutic implications) of abrogation/modulation of IRES-mediated expression
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