@article{2cb683323a964f3c8c35b7ca371107a8,
title = "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.",
keywords = "RNA hybrid, cap-snatching, chimeric proteins, gene origination, influenza, segmented negative-strand RNA viruses, uORFs, upstream AUG, viral RNA, viral evolution",
author = "Ho, {Jessica Sook Yuin} and Matthew Angel and Yixuan Ma and Elizabeth Sloan and Guojun Wang and Carles Martinez-Romero and Marta Alenquer and Vladimir Roudko and Liliane Chung and Simin Zheng and Max Chang and Yesai Fstkchyan and Sara Clohisey and Dinan, {Adam M.} and James Gibbs and Robert Gifford and Rong Shen and Quan Gu and Nerea Irigoyen and Laura Campisi and Cheng Huang and Nan Zhao and Jones, {Joshua D.} and {van Knippenberg}, Ingeborg and Zeyu Zhu and Natasha Moshkina and L{\'e}a Meyer and Justine Noel and Zuleyma Peralta and Veronica Rezelj and Robyn Kaake and Brad Rosenberg and Bo Wang and Jiajie Wei and Slobodan Paessler and Wise, {Helen M.} and Jeffrey Johnson and Alessandro Vannini and Amorim, {Maria Jo{\~a}o} and Baillie, {J. Kenneth} and Miraldi, {Emily R.} and Christopher Benner and Ian Brierley and Paul Digard and Marta {\L}uksza and Firth, {Andrew E.} and Nevan Krogan and Greenbaum, {Benjamin D.} and MacLeod, {Megan K.} and {van Bakel}, Harm and Adolfo Garc{\`i}a-Sastre and Yewdell, {Jonathan W.} and Edward Hutchinson and Ivan Marazzi",
note = "Funding Information: We thank the Genomics and Mouse facility at Icahn School of Medicine at Mount Sinai, the Global Health and Emerging Pathogens Institute (GHEPI) at Mount Sinai, and the entire Marazzi Lab team. The authors would also like to thank Ervin Fodor, University of Oxford for support and critical comments on the project; Svenja Hester, Benjamin Thomas, and Shabaz Mohammed of the Advanced Proteomics Facility, University of Oxford for proteomics; Elly Gaunt, University of Edinburgh and Michael Goodin, University of Kentucky, for critical reading of the manuscript; and staff within the Institute of Infection, Immunity, and Inflammation Flow Cytometry Facility, the Central Research Facility at the University of Glasgow, Thomas Purnell of the Institute of Infection, Immunity and Inflammation, University of Glasgow and Dimitris Athineos of the Beatson Institute for technical assistance and discussion. I.M. is supported by the Burroughs Wellcome Fund (United States; 1017892 ) and by the Chan Zuckerberg Initiative (United States; 2018-191895 ). I.M. and H.v.B. are supported by the NIH (United States; R01AI113186 ). A.G.-S. and I.M. are supported by the NIH ( U19AI135972 FLUOMICS ). E.H., E.S., and Q.G. are supported by an MRC (United Kingdom) Career Development Award ( MR/N008618/1 ), and E.H. carried out proteomics work when funded by an MRC Programme Grant to Prof. Ervin Fodor, University of Oxford ( MR/K000241/1 ). V.R. and I.v.K. were supported by a Wellcome Trust (United Kingdom) Senior Investigator award ( 099220/Z/12/Z ) awarded to Prof. Richard M. Elliott, University of Glasgow. R.G. and Q.G. were supported by the MRC ( MC_UU_12014/12 ). J.K.B. was supported by a Wellcome Trust Intermediate Clinical Fellowship ( 103258/Z/13/Z ), a Wellcome-Beit Prize ( 103258/Z/13/A ), and the UK Intensive Care Society . J.K.B. and S.C. acknowledge the BBSRC (United Kingdom) Institute Strategic Programme Grant to the Roslin Institute. B.W. was supported by a SHIELD ( MR/N02995X/1 ) Edinburgh Global Research Scholarship. A.E.F. was supported by the Wellcome Trust ( 106207 ) and European Research Council (European Union; 646891 ). I.B., P.D., and H.M.W. were supported by an MRC project grant ( MR/M011747/1 ). P.D. was supported by the BBSRC Institute Strategic Programme ( BB/J004324/1 and BB/P013740/1 ). J.D.J. was funded by a Wellcome Trust PhD scholarship. M. Alenquer and M.J.A. were supported by the FCT (Portugal) award PTDC/BIA-CEL/32211/2017 and IF/00899/2013 , respectively. M.K.M. was supported by a Wellcome Investigator Award ( 210703/Z/18/Z ). Publisher Copyright: {\textcopyright} 2020 The Authors",
year = "2020",
month = jun,
day = "25",
doi = "10.1016/j.cell.2020.05.035",
language = "English (US)",
volume = "181",
pages = "1502--1517.e23",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "7",
}