Structural basis for IFN antagonism by human respiratory syncytial virus nonstructural protein 2

Jingjing Pei, Nicole D. Wagner, Angela J. Zou, Srirupa Chatterjee, Dominika Borek, Aidan R. Cole, Preston J. Kim, Christopher F. Basler, Zbyszek Otwinowski, Michael L. Gross, Gaya K. Amarasinghe, Daisy W. Leung

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


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.

Original languageEnglish (US)
Article numbere2020587118
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number10
StatePublished - Mar 9 2021


  • IFN antagonist
  • NS2
  • Nonstructural protein
  • RSV

ASJC Scopus subject areas

  • General


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