Ranum, J. N. et al. (2024) Cryptic proteins translated from deletion-containing viral genomes dramatically expand the influenza virus proteome. Nucleic Acids Research, (doi: 10.1093/nar/gkae133) (PMID:38407436) (Early Online Publication)
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Abstract
Productive infections by RNA viruses require faithful replication of the entire genome. Yet many RNA viruses also produce deletion-containing viral genomes (DelVGs), aberrant replication products with large internal deletions. DelVGs interfere with the replication of wild-type virus and their presence in patients is associated with better clinical outcomes. The DelVG RNA itself is hypothesized to confer this interfering activity. DelVGs antagonize replication by out-competing the full-length genome and triggering innate immune responses. Here, we identify an additionally inhibitory mechanism mediated by a new class of viral proteins encoded by DelVGs. We identified hundreds of cryptic viral proteins translated from DelVGs. These DelVG-encoded proteins (DPRs) include canonical viral proteins with large internal deletions, as well as proteins with novel C-termini translated from alternative reading frames. Many DPRs retain functional domains shared with their full-length counterparts, suggesting they may have activity during infection. Mechanistic studies of DPRs derived from the influenza virus protein PB2 showed that they poison replication of wild-type virus by acting as dominant-negative inhibitors of the viral polymerase. These findings reveal that DelVGs have a dual inhibitory mechanism, acting at both the RNA and protein level. They further show that DPRs have the potential to dramatically expand the functional proteomes of diverse RNA viruses.
| Item Type: | Articles |
|---|---|
| Additional Information: | Burroughs Wellcome Fund Investigator in the Pathogenesis of Infectious Disease (to A.M.); H.I. Romnes Faculty Fellow funded by the Wisconsin Alumni Research Foundation (to A.M.); Vilas Faculty Mid-Career Investigator Award (to A.M.); National Science Foundation GRFP [DGE-1747503 to M.P.L.]; National Institute of General Medicine [R35GM147031to A.B.R.]; PATHS program at University of California San Diego (to M.G.); Defense Advanced Research Projects Agency [DARPA-16-35-INTERCEPT-FP-018 to C.B.B.]; National Institute of Allergy and Infectious Diseases [R01AI139246 to C.B.B.]; core funding to the MRC-University of Glasgow Centre for Virus Research [MC_UU_12014/9, MC_UU_12014/12, d MC_UU_00034/5]. Funding for open access charge: HI Romnes Faculty Fellow award. |
| Status: | Early Online Publication |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Conley, Dr Michaela and Smollett, Dr Katherine and Da Silva Filipe, Dr Ana and Sloan, Dr Elizabeth and Hutchinson, Dr Edward and Orton, Dr Richard |
| Authors: | Ranum, J. N., Ledwith, M. P., Alnaji, F. G., Diefenbacher, M., Orton, R., Sloan, E., Güereca, M., Feltman, E. M., Smollett, K., da Silva Filipe, A., Conley, M., Russell, A. B., Brooke, C. B., Hutchinson, E., and Mehle, A. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research |
| Journal Name: | Nucleic Acids Research |
| Publisher: | Oxford University Press |
| ISSN: | 0305-1048 |
| ISSN (Online): | 1362-4962 |
| Published Online: | 26 February 2024 |
| Copyright Holders: | Copyright © 2024 The Authors |
| First Published: | First published in Nucleic Acids Research 2024 |
| Publisher Policy: | Reproduced under a Creative Commons License |
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