Cell . Hybrid Gene Origination Creates Human-Virus Chimeric Proteins During Infection

[tetano]

Cell


. 2020 Jun 17;S0092-8674(20)30630-9.
doi: 10.1016/j.cell.2020.05.035. Online ahead of print.
Hybrid Gene Origination Creates Human-Virus Chimeric Proteins During Infection


Jessica Sook Yuin Ho ¹ , Matthew Angel ² , Yixuan Ma ¹ , Elizabeth Sloan ³ , Guojun Wang ⁴ , Carles Martinez-Romero ⁵ , Marta Alenquer ⁶ , Vladimir Roudko ⁷ , Liliane Chung ⁸ , Simin Zheng ¹ , Max Chang ⁹ , Yesai Fstkchyan ¹ , Sara Clohisey ⁸ , Adam M Dinan ¹⁰ , James Gibbs ² , Robert Gifford ³ , Rong Shen ¹¹ , Quan Gu ³ , Nerea Irigoyen ¹⁰ , Laura Campisi ¹ , Cheng Huang ¹² , Nan Zhao ¹ , Joshua D Jones ¹⁰ , Ingeborg van Knippenberg ³ , Zeyu Zhu ¹ , Natasha Moshkina ¹ , L?a Meyer ³ , Justine Noel ¹ , Zuleyma Peralta ¹³ , Veronica Rezelj ³ , Robyn Kaake ¹⁴ , Brad Rosenberg ¹ , Bo Wang ⁸ , Jiajie Wei ² , Slobodan Paessler ¹² , Helen M Wise ⁸ , Jeffrey Johnson ¹⁵ , Alessandro Vannini ¹⁶ , Maria Jo?o Amorim ⁶ , J Kenneth Baillie ⁸ , Emily R Miraldi ¹⁷ , Christopher Benner ⁹ , Ian Brierley ¹⁰ , Paul Digard ⁸ , Marta Łuksza ¹³ , Andrew E Firth ¹⁰ , Nevan Krogan ¹⁴ , Benjamin D Greenbaum ⁷ , Megan K MacLeod ¹⁸ , Harm van Bakel ¹³ , Adolfo Garc?a-Sastre ⁵ , Jonathan W Yewdell ² , Edward Hutchinson ¹⁹ , Ivan Marazzi ²⁰



Affiliations

• PMID: 32559462
• DOI: 10.1016/j.cell.2020.05.035

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.

Keywords: RNA hybrid; cap-snatching; chimeric proteins; gene origination; influenza; segmented negative-strand RNA viruses; uORFs; upstream AUG; viral RNA; viral evolution.