Distinct roles for the IIId2 sub-domain in pestivirus and picornavirus internal ribosome entry sites.

Margaret M Willcocks,Salmah Zaini,Thomas Bruun Rasmussen,Nathalie Chamond,Delphine Allouche,Bruno Sargueil,Noemie Rajagopalan,Nana A Davids,Ulrik Fahnøe,Graham J Belsham,Nicolas Locker,Johanne Hadsbjerg,Nathalie Ulryck,Lisa O Roberts

doi:10.1093/nar/gkx991

Margaret M Willcocks, Salmah Zaini + Show 12 more

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https://doi.org/10.1093/nar/gkx991

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Viral internal ribosomes entry site (IRES) elements coordinate the recruitment of the host translation machinery to direct the initiation of viral protein synthesis. Within hepatitis C virus (HCV)-like IRES elements, the sub-domain IIId(1) is crucial for recruiting the 40S ribosomal subunit. However, some HCV-like IRES elements possess an additional sub-domain, termed IIId2, whose function remains unclear. Herein, we show that IIId2 sub-domains from divergent viruses have different functions. The IIId2 sub-domain present in Seneca valley virus (SVV), a picornavirus, is dispensable for IRES activity, while the IIId2 sub-domains of two pestiviruses, classical swine fever virus (CSFV) and border disease virus (BDV), are required for 80S ribosomes assembly and IRES activity. Unlike in SVV, the deletion of IIId2 from the CSFV and BDV IRES elements impairs initiation of translation by inhibiting the assembly of 80S ribosomes. Consequently, this negatively affects the replication of CSFV and BDV. Finally, we show that the SVV IIId2 sub-domain is required for efficient viral RNA synthesis and growth of SVV, but not for IRES function. This study sheds light on the molecular evolution of viruses by clearly demonstrating that conserved RNA structures, within distantly related RNA viruses, have acquired different roles in the virus life cycles.

Highlights

The initiation of protein synthesis on the majority of cellular mRNAs is achieved via a cap-dependent scanning mechanism, reviewed in [1]
We previously reported that Seneca valley virus (SVV), a picornavirus, harbours an internal ribosomes entry site (IRES) element that is functionally related to the hepatitis C virus (HCV)
While the sub-domains IIId of HCV and IIId1 of classical swine fever virus (CSFV) are important for ribosome binding, the additional SVV IRES domain IIId2 is dispensable for the IRES activity [28]

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The initiation of protein synthesis on the majority of cellular mRNAs is achieved via a cap-dependent scanning mechanism, reviewed in [1]. The 5 -cap structure of cellular mRNAs is first recognized by the eukaryotic initiation factor complex 4F (eIF4F), comprising eIF4E, eIF4A and eIF4G [1]. EIF4F recruits onto the mRNA a 43S pre-initiation complex consisting of a 40S ribosomal subunit, the ternary complex eIF2-GTP-MettRNAi, eIF3, eIF1 and eIF1A, thereby priming the canonical scanning mechanism [1]. Initiation of translation on certain viral RNAs (e.g. from picornaviruses and pestiviruses) and some cellular mRNAs occurs via a capindependent mechanism in which IRES elements within the RNA recruit the ribosome internally, bypassing the need for some of the eIFs and a 5 -cap recognition event [2].

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