Making ends meet: Specialized translation of viral mRNAs lacking canonical features

Translation initiation in eukaryotic cells is usually driven by recognition of a 5′ cap and a 3′ poly(A) tail, which cooperate through interactions with eukaryotic initiation factors (eIFs) and poly(A)-binding protein (PABP) to promote mRNA circularization and efficient ribosome recruitment. However, many viral RNAs lack one or both of these canonical features and must use alternative strategies to access the host translational machinery. Diverse mechanisms are used to bypass cap dependence, including internal ribosome entry sites that recruit ribosomal subunits with variable requirements for canonical initiation factors as well as viral protein genome-linked strategies that functionally substitute for the cap by engaging components of the eIF4F complex. For viral mRNAs lacking poly(A) tails, translation can be supported by long-range RNA-RNA interactions that mediate 5′-3′ communication and viral or host proteins that replace PABP to facilitate closed-loop formation. Emerging examples, including the host protein ATXN2L during reovirus infection, illustrate how viruses use or mimic cellular factors to promote selective translation. Collectively, these strategies reveal fundamental principles of mRNA circularization and translational control, highlighting the dynamic interplay between viral and host machinery in regulating protein synthesis. • mRNA closed-loop formation by engagement of the host translation machinery at the RNA termini is fundamental for eukaryotic translation. • Viruses encoding mRNAs lacking a 5′ cap use internal ribosome entry sites and VPg proteins to access the host translation machinery. • Long distance RNA-RNA interactions or engagement of 3′ termini by a PABP surrogate promotes nonpolyadenylated viral mRNA translation. • Host protein ATXN2L promotes reovirus nonpolyadenylated mRNA translation.