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| Title | Distinct non-canonical translation initiation modes arise for specific host and viral mRNAs during poxvirus-induced shutoff. |
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| Journal, issue, pages | Nat Microbiol, Vol. 10, Issue 6, Page 1535-1549, Year 2025 |
| Publish date | May 28, 2025 |
 Authors | Chorong Park / Aaron J Ferrell / Nathan Meade / Peter S Shen / Derek Walsh /  |
| PubMed Abstract | Many viruses potently inhibit host protein synthesis, termed host shutoff, while employing strategies to sustain their own translation. How and why certain host mRNAs continue to be translated at ...Many viruses potently inhibit host protein synthesis, termed host shutoff, while employing strategies to sustain their own translation. How and why certain host mRNAs continue to be translated at later infection stages remains unclear. Here, using RNAseq and polysome profiling, we show that during shutoff by vaccinia virus (VacV), several host mRNAs increase in polysome occupancy but only a few, primarily JUN that encodes the Jun transcription factor, result in increased protein abundance across multiple cell lines. While dispensable for Jun production, translation of viral mRNAs depended on the small ribosomal protein, Receptor for Activated C Kinase 1 (RACK1) and the eukaryotic Initiation Factor, eIF3. These differential eIF3 dependencies are associated with structurally distinct 5' untranslated regions in viral versus JUN mRNAs. Cryo-electron microscopy structures of 40S ribosomes from mock-infected or VacV-infected cells showed that when bound to eIF3, the rotational range of the RACK1-containing 40S head domain broadens during infection. Our data reveal how eIF3-bound 40S ribosomes are remodelled late in infection and the distinct strategies of translation initiation that arise during shutoff to produce host and viral proteins required for poxvirus spread. |
 External links | Nat Microbiol / PubMed:40437296 |
| Methods | EM (single particle) |
| Resolution | 2.8 - 6.2 Å |
| Structure data |  EMDB-46432: eIF3-bound 40S, state 1, from VacV infected cells  EMDB-46447: eIF3-bound 40S, state 2, from VacV infected cells  EMDB-46449: Free 40S, state 1, from VacV infected cells  EMDB-46450: Free 40S, state 2, from VacV infected cells  EMDB-48640: eIF3-bound 40S consensus structure, from VacV infected cells  EMDB-48641: Free 40S consensus structure, from VacV infected cells  EMDB-48642: eIF3-bound 40S consensus structure, from mock infected cells  EMDB-48643: Free 40S consensus structure, from mock infected cells  EMDB-48644: Free 40S, state 1, from mock infected cells  EMDB-48645: Free 40S, state 2, from mock infected cells  EMDB-48646: eIF3-bound 40S, state 1, from mock infected cells  EMDB-48647: eIF3-bound 40S, state 2, from mock infected cells |
| Source |
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Homo sapiens (human)