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JSY Ho, M Angel, Y Ma, E Sloan, G Wang, C Martinez-Romero, M Alenquer, V Roudko, L Chung, S Zheng, M Chang, Y Fstkchyan, S Clohisey, AM Dinan, J Gibbs, R Gifford, R Shen, Q Gu, N Irigoyen, L Campisi, C Huang, N Zhao, JD Jones, I van Knippenberg, Z Zhu, N Moshkina, L Meyer, J Noel, Z Peralta, V Rezelj, R Kaake, B Rosenberg, B Wang, J Wei, S Paessler, HM Wise, J Johnson, A Vannini, MJ Amorim, JK Baillie, ER Miraldi, C Benner, I Brierley, P Digard, M Łuksza, AE Firth, N Krogan, BD Greenbaum, MK MacLeod, H van Bakel, A Garcìa-Sastre, JW Yewdell, E Hutchinson and I Marazzi
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.
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