Structural basis for IFN antagonism by human respiratory syncytial virus nonstructural protein 2
- 9 March 2021
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 118 (10)
- https://doi.org/10.1073/pnas.2020587118
Abstract
Human respiratory syncytial virus (RSV) nonstructural protein 2 (NS2) inhibits host interferon (IFN) responses stimulated by RSV infection by targeting early steps in the IFN-signaling pathway. But the molecular mechanisms related to how NS2 regulates these processes remain incompletely understood. To address this gap, here we solved the X-ray crystal structure of NS2. This structure revealed a unique fold that is distinct from other known viral IFN antagonists, including RSV NS1. We also show that NS2 directly interacts with an inactive conformation of the RIG-I–like receptors (RLRs) RIG-I and MDA5. NS2 binding prevents RLR ubiquitination, a process critical for prolonged activation of downstream signaling. Structural analysis, including by hydrogen-deuterium exchange coupled to mass spectrometry, revealed that the N terminus of NS2 is essential for binding to the RIG-I caspase activation and recruitment domains. N-terminal mutations significantly diminish RIG-I interactions and result in increased IFNβ messenger RNA levels. Collectively, our studies uncover a previously unappreciated regulatory mechanism by which NS2 further modulates host responses and define an approach for targeting host responses.Funding Information
- HHS | NIH | National Institute of Allergy and Infectious Diseases (R01AI107056)
- HHS | NIH | National Institute of Allergy and Infectious Diseases (R01AI140758)
- HHS | NIH | National Institute of Allergy and Infectious Diseases (P01AI120943)
- HHS | NIH | National Institute of Allergy and Infectious Diseases (R01AI114654)
- HHS | NIH | National Institute of Allergy and Infectious Diseases (U19AI109945)
- HHS | NIH | National Institute of Allergy and Infectious Diseases (U19AI109664)
- HHS | NIH | National Institute of General Medical Sciences (P41GM103422)
- HHS | NIH | National Institute of General Medical Sciences (R24GM136766)
- American Heart Association (15POST25140009)
- Children's Discovery Institute (PDII2018702)
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