Abstract
Internal ribosome entry sites (IRES) are utilized by a subset of cellular and viral mRNAs to initiate translation during cellular stress and virus infection when canonical cap-dependent translation is compromised. The intergenic region (IGR) IRES of the Dicistroviridae uses a streamlined mechanism in which it can directly recruit the ribosome in the absence of initiation factors and initiates translation using a non-AUG codon. A subset of IGR IRESs including that from the honey bee viruses can also direct translation of an overlapping +1 frame gene. In this study, we systematically examined cellular conditions that lead to IGR IRES-mediated 0 and +1 frame translation in Drosophila S2 cells. Towards this, a novel bicistronic reporter that exploits the 2A “stop-go” peptide was developed to allow the detection of IRES-mediated translation in vivo. Both 0 and +1 frame translation by the IGR IRES are stimulated under a number of cellular stresses and in S2 cells infected by cricket paralysis virus, demonstrating a switch from cap-dependent to IRES-dependent translation. The regulation of the IGR IRES mechanism ensures that both 0 frame viral structural proteins and +1 frame ORFx protein are optimally expressed during virus infection.
Highlights
The majority of eukaryotic mRNAs utilize a cap-dependent scanning mechanism to recruit the ribosome, whereas internal ribosome entry sites are cis-acting elements that direct recruitment of the ribosome in a 59 end independent manner
For some RNA viruses such as picornaviruses, specific steps in cap-dependent translation are compromised increasing the available pool of ribosomes and initiations factors for viral Internal ribosome entry sites (IRES) translation
DNA viruses like human cytomegalovirus (HCMV), host translation is not impaired and virus replication relies on stimulation of cap-dependent translation machinery and increases in initiation factors concentration [48,49]
Summary
The majority of eukaryotic mRNAs utilize a cap-dependent scanning mechanism to recruit the ribosome, whereas internal ribosome entry sites are cis-acting elements that direct recruitment of the ribosome in a 59 end independent manner. IRESs, in general, adopt RNA structures that recruit specific translation initiation factors or IRES trans-acting factors (ITAFs) that contribute to ribosome recruitment and translation initiation [3,4]. It is proposed that the IRES allows for preferential translation of an mRNA during cellular stress or viral infection when overall cap-dependent translation is compromised [1,7]. Coordination of this switch from cap-dependent translation to IRES-dependent translation is an important strategy utilized by some positive strand RNA viruses to efficiently hijack the ribosome for productive viral protein synthesis [1,7]
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