Hybrid Gene Origination Creates Human-Virus Chimeric Proteins during Infection.

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.

• Authors: 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 Campisi, Cheng 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
• Journal: Cell (Cell) Vol. 181 Issue 7 Pg. 1502-1517.e23 (06 25 2020) ISSN: 1097-4172 [Electronic] United States
• PMID: 32559462 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• 5' Untranslated Regions
• Mutant Chimeric Proteins
• RNA Caps
• RNA, Messenger
• RNA, Viral
• Recombinant Fusion Proteins
• Viral Proteins
• RNA-Dependent RNA Polymerase

Topics

• 5' Untranslated Regions (genetics)
• Animals
• Cattle
• Cell Line
• Cricetinae
• Dogs
• Humans
• Influenza A virus (metabolism)
• Mice
• Mutant Chimeric Proteins (genetics, metabolism)
• Open Reading Frames (genetics)
• RNA Caps (genetics, metabolism)
• RNA Virus Infections (genetics, metabolism)
• RNA Viruses (genetics)
• RNA, Messenger (genetics, metabolism)
• RNA, Viral (metabolism)
• RNA-Dependent RNA Polymerase (genetics, metabolism)
• Recombinant Fusion Proteins (genetics, metabolism)
• Transcription, Genetic (genetics)
• Viral Proteins (metabolism)
• Virus Replication (genetics)