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

Published version
Peer-reviewed

Type

Article

Change log

Authors

Ho, Jessica Sook Yuin 
Angel, Matthew 
Ma, Yixuan 
Sloan, Elizabeth 
Wang, Guojun 

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.

Description

Keywords

RNA hybrid, cap-snatching, chimeric proteins, gene origination, influenza, segmented negative-strand RNA viruses, uORFs, upstream AUG, viral RNA, viral evolution, 5' Untranslated Regions, Animals, Cattle, Cell Line, Cricetinae, Dogs, Humans, Influenza A virus, Mice, Mutant Chimeric Proteins, Open Reading Frames, RNA Caps, RNA Virus Infections, RNA Viruses, RNA, Messenger, RNA, Viral, RNA-Dependent RNA Polymerase, Recombinant Fusion Proteins, Transcription, Genetic, Viral Proteins, Virus Replication

Journal Title

Cell

Conference Name

Journal ISSN

0092-8674
1097-4172

Volume Title

181

Publisher

Elsevier BV
Sponsorship
Wellcome Trust (106207/Z/14/Z)
European Research Council (646891)
Medical Research Council (MR/M011747/1)
Wellcome Trust (202797/Z/16/Z)