Trans-kingdom mimicry underlies ribosome customization by a poxvirus kinase

The poxvirus vaccinia virus phosphorylates serine/threonine residues in the human small ribosomal subunit RACK1, converting it to a plant-like state to favour translation of poxvirus mRNAs Mimicry that spreads the pox It has been proposed that ribosomes have the capacity to control mRNA-specific translation by changes in their subunit composition or post-translational modifications. Derek Walsh and colleagues reveal a new way that viruses usurp the cellular machinery to facilitate their replication. They show that poxviruses customize host ribosomes to boost translation of viral mRNAs. The vaccinia virus phosphorylates serine/threonine residues in the ribosomal subunit RACK1, creating a RACK1 loop with a negative charge. This results in the preferential translation of poxvirus mRNAs that carry adenosine repeats in the 5′ UTR, which act as translational enhancers. Ribosomes have the capacity to selectively control translation through changes in their composition that enable recognition of specific RNA elements 1 . However, beyond differential subunit expression during development 2 , 3 , evidence for regulated ribosome specification within individual cells has remained elusive 1 . Here we report that a poxvirus kinase phosphorylates serine/threonine residues in the human small ribosomal subunit protein, receptor for activated C kinase (RACK1), that are not phosphorylated in uninfected cells or cells infected by other viruses. These modified residues cluster in an extended loop in RACK1, phosphorylation of which selects for translation of viral or reporter mRNAs with 5′ untranslated regions that contain adenosine repeats, so-called polyA-leaders. Structural and phylogenetic analyses revealed that although RACK1 is highly conserved, this loop is variable and contains negatively charged amino acids in plants, in which these leaders act as translational enhancers. Phosphomimetics and inter-species chimaeras have shown that negative charge in the RACK1 loop dictates ribosome selectivity towards viral RNAs. By converting human RACK1 to a charged, plant-like state, poxviruses remodel host ribosomes so that adenosine repeats erroneously generated by slippage of the viral RNA polymerase 4 confer a translational advantage. Our findings provide insight into ribosome customization through trans-kingdom mimicry and the mechanics of species-specific leader activity that underlie poxvirus polyA-leaders 4 .