Hybrid Gene Origination Creates Human-Virus Chimeric Proteins during Infection

Jessica Sook Yuin Ho, Matthew Angel, Yixuan Ma, Elizabeth Sloan, Guojun Wang, Carles Martinez-Romero, Marta Alenquer, Vladimir Roudko, Liliane Chung, Simin Zheng, Max Chang, Yesai Fstkchyan, Sara Clohisey, Adam M. Dinan, James Gibbs, Robert Gifford, Rong Shen, Quan Gu, Nerea Irigoyen, Laura CampisiCheng Huang, Nan Zhao, Joshua D. Jones, Ingeborg van Knippenberg, Zeyu Zhu, Natasha Moshkina, Léa Meyer, Justine Noel, Zuleyma Peralta, Veronica Rezelj, Robyn Kaake, Brad Rosenberg, Bo Wang, Jiajie Wei, Slobodan Paessler, Helen M. Wise, Jeffrey Johnson, Alessandro Vannini, Maria João Amorim, J. Kenneth Baillie, Emily R. Miraldi, Christopher Benner, Ian Brierley, Paul Digard, Marta Łuksza, Andrew E. Firth, Nevan Krogan, Benjamin D. Greenbaum, Megan K. MacLeod, Harm van Bakel, Adolfo Garcìa-Sastre, Jonathan W. Yewdell, Edward Hutchinson, Ivan Marazzi

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

RNA viruses are a major human health threat. The life cycles of many highly pathogenic RNA viruses like influenza A virus (IAV) and Lassa virus depends on host mRNA, because viral polymerases cleave 5′-m7G-capped host transcripts to prime viral mRNA synthesis (“cap-snatching”). We hypothesized that start codons within cap-snatched host transcripts could generate chimeric human-viral mRNAs with coding potential. We report the existence of this mechanism of gene origination, which we named “start-snatching.” Depending on the reading frame, start-snatching allows the translation of host and viral “untranslated regions” (UTRs) to create N-terminally extended viral proteins or entirely novel polypeptides by genetic overprinting. We show that both types of chimeric proteins are made in IAV-infected cells, generate T cell responses, and contribute to virulence. Our results indicate that during infection with IAV, and likely a multitude of other human, animal and plant viruses, a host-dependent mechanism allows the genesis of hybrid genes.

Original languageEnglish (US)
Pages (from-to)1502-1517.e23
JournalCell
Volume181
Issue number7
DOIs
StatePublished - Jun 25 2020

Keywords

  • RNA hybrid
  • cap-snatching
  • chimeric proteins
  • gene origination
  • influenza
  • segmented negative-strand RNA viruses
  • uORFs
  • upstream AUG
  • viral RNA
  • viral evolution

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Ho, J. S. Y., Angel, M., Ma, Y., Sloan, E., Wang, G., Martinez-Romero, C., Alenquer, M., Roudko, V., Chung, L., Zheng, S., Chang, M., Fstkchyan, Y., Clohisey, S., Dinan, A. M., Gibbs, J., Gifford, R., Shen, R., Gu, Q., Irigoyen, N., ... Marazzi, I. (2020). Hybrid Gene Origination Creates Human-Virus Chimeric Proteins during Infection. Cell, 181(7), 1502-1517.e23. https://doi.org/10.1016/j.cell.2020.05.035