Lytras, S. et al. (2023) Resurrection of 2′-5′-oligoadenylate synthetase 1 (OAS1) from the ancestor of modern horseshoe bats blocks SARS-CoV-2 replication. PLoS Biology, 21(11), e3002398. (doi: 10.1371/journal.pbio.3002398) (PMID:38015855)
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Abstract
The prenylated form of the human 2′-5′-oligoadenylate synthetase 1 (OAS1) protein has been shown to potently inhibit the replication of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the virus responsible for the Coronavirus Disease 2019 (COVID-19) pandemic. However, the OAS1 orthologue in the horseshoe bats (superfamily Rhinolophoidea), the reservoir host of SARS-related coronaviruses (SARSr-CoVs), has lost the prenylation signal required for this antiviral activity. Herein, we used an ancestral state reconstruction approach to predict and reconstitute in vitro, the most likely OAS1 protein sequence expressed by the Rhinolophoidea common ancestor prior to its prenylation loss (RhinoCA OAS1). We exogenously expressed the ancient bat protein in vitro to show that, unlike its non-prenylated horseshoe bat descendants, RhinoCA OAS1 successfully blocks SARS-CoV-2 replication. Using protein structure predictions in combination with evolutionary hypothesis testing methods, we highlight sites under unique diversifying selection specific to OAS1’s evolution in the Rhinolophoidea. These sites are located near the RNA-binding region and the C-terminal end of the protein where the prenylation signal would have been. Our results confirm that OAS1 prenylation loss at the base of the Rhinolophoidea clade ablated the ability of OAS1 to restrict SARSr-CoV replication and that subsequent evolution of the gene in these bats likely favoured an alternative function. These findings can advance our understanding of the tightly linked association between SARSr-CoVs and horseshoe bats.
| Item Type: | Articles |
|---|---|
| Additional Information: | This study was supported by Medical Research Council (https://www.ukri.org/councils/mrc) awards MR/P022642/1 (SJW), MR/V01157X/1 (SJW) and MC_UU_12014/12 (JH). SS holds a Daphne Jackson Fellowship funded by Medical Research Scotland. |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Davies, Miss Emma and Stewart, Mr Douglas and Swingler, Dr Simon and Wilson, Professor Sam and Wickenhagen, Mr Arthur and Sugrue, Dr Elena and Hughes, Dr Joseph and Lytras, Mr Spyros and Jackson Ireland, Hollie and Sims, Miss Anna |
| Creator Roles: | Lytras, S.Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Software, Validation, Visualization, Writing – original draft, Writing – review and editing Wickenhagen, A.Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing – original draft, Writing – review and editing Sugrue, E.Conceptualization, Formal analysis, Investigation, Methodology, Validation, Writing – original draft, Writing – review and editing Stewart, D.Formal analysis, Investigation, Methodology, Validation, Visualization, Writing – review and editing Swingler, S.Data curation, Formal analysis, Investigation, Methodology, Validation, Writing – review and editing Sims, A.Data curation, Formal analysis, Investigation, Methodology, Validation, Writing – review and editing Jackson Ireland, H.Investigation, Validation, Writing – review and editing Davies, E.Investigation, Validation, Writing – review and editing Hughes, J.Conceptualization, Supervision, Writing – review and editing Wilson, S.Conceptualization, Funding acquisition, Supervision, Writing – review and editing |
| Authors: | Lytras, S., Wickenhagen, A., Sugrue, E., Stewart, D. G., Swingler, S., Sims, A., Jackson Ireland, H., Davies, E. L., Ludlam, E. M., Li, Z., Hughes, J., and Wilson, S. J. |
| College/School: | College of Medical Veterinary and Life Sciences College of Medical Veterinary and Life Sciences > School of Infection & Immunity College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research |
| Journal Name: | PLoS Biology |
| Publisher: | Public Library of Science |
| ISSN: | 1544-9173 |
| ISSN (Online): | 1545-7885 |
| Copyright Holders: | Copyright © 2023 The Authors |
| First Published: | First published in PLoS Biology 21(11):e3002398 |
| Publisher Policy: | Reproduced under a Creative Commons License |
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