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Hybrid Gene Origination Creates Human-Virus Chimeric Protein During Infection

Research output: Contribution to journalArticle

  • Jessica Sook Yuin Ho
  • Matthew Angel
  • Yixuan Ma
  • Elizabeth Sloan
  • Guojun Wang
  • Carles Martinez-Romero
  • Marta Alenquer
  • Vladimir Roudko
  • Simin Zheng
  • Max Chang
  • Yesai Fstkchyan
  • Adam M. Dinan
  • James Gibbs
  • Robert Gifford
  • Rong Shen
  • Quan Gu
  • Nerea Irigoyen
  • Laura Campisi
  • Cheng Huang
  • Nan Zhao
  • 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
  • Jeffrey Johnson
  • Alessandro Vannini
  • Maria Joao Amorim
  • Emily R. Miraldi
  • Christopher Benner
  • Ian Brierley
  • 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

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Original languageEnglish
JournalCell
Early online date18 Jun 2020
DOIs
Publication statusE-pub ahead of print - 18 Jun 2020

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.

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