Hybrid Gene Origination Creates Human-Virus Chimeric Protein 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, Josh Jones, Ingeborg van Knippenberg, Zeyu Zhu , Natasha Moshkina, Lea Meyer , Justine Noel, Zuleyma Peralta, Veronica Rezelji, Robyn Kaake, Brad Rosenberg, Bo Wang, Jiajie Wei, Slobodan Paessler, Helen Wise, Jeffrey Johnson, Alessandro Vannini, Maria Joao Amorim, Kenneth Baillie, Emily R. Miraldi, Christopher Benner, Ian Brierley, Paul Digard, Marta Luksza, Andrew E Firth, Nevan J Krogan, Benjamin D. Greenbaum, Megan K. MacLeod, Harm van Bakel, Adolfo García-Sastre, Jonathan W Yewdell, Edward Hutchinson, Ivan Marrazi

Research output: Contribution to journalArticlepeer-review

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, as viral polymerases cleave 5’-m7G-capped host transcripts to primeviral 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, that we named ‘start-snatching’. Depending on the reading frame, start-snatching allows the translation of host and viral “untranslated regions” (UTRs) to create Nterminally
extended viral proteins or entirely novel polypeptides by genetic
overprinting. We show that both types of chimeric proteins are made in IAVinfected
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
Pages (from-to)1502-1517
JournalCell
Volume181
Issue number7
Early online date18 Jun 2020
DOIs
Publication statusPublished - 25 Jun 2020

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