Structural basis for dsRNA recognition and interferon antagonism by Ebola VP35

• Published in: Nature structural & molecular biology Vol. 17; no. 2; pp. 165 - 172
• Main Authors: Amarasinghe, Gaya K, Leung, Daisy W, Prins, Kathleen C, Borek, Dominika M, Farahbakhsh, Mina, Tufariello, JoAnn M, Ramanan, Parameshwaran, Nix, Jay C, Helgeson, Luke A, Otwinowski, Zbyszek, Honzatko, Richard B, Basler, Christopher F
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-02-2010; Nature Publishing Group
• Subjects: 631/250/516; 631/45/127/1212; 631/45/500; 631/45/612/1256; Binding Sites; Biochemistry; Biological Microscopy; Biomedical and Life Sciences; CRYSTAL STRUCTURE; Crystallography, X-Ray; DEAD Box Protein 58; DEAD-box RNA Helicases - immunology; Ebola virus; Ebola virus infections; Ebolavirus - chemistry; Ebolavirus - immunology; Genetic aspects; Immune Evasion; IN VIVO; INTERFERON; Interferons - antagonists & inhibitors; Kinases; Life Sciences; MATERIALS SCIENCE; Membrane Biology; Models, Molecular; Physiological aspects; POLYMERASES; Protein Binding; Protein Structure; Protein Structure, Tertiary; PROTEINS; Receptors, Immunologic; RESIDUES; Risk factors; RNA; RNA, Double-Stranded - metabolism; RNA-Binding Proteins - chemistry; RNA-Binding Proteins - metabolism; Sensors; Signal transduction; Structure; Viral proteins; Viral Regulatory and Accessory Proteins - chemistry; Viral Regulatory and Accessory Proteins - metabolism; United States
• ISSN: 1545-9993; 1545-9985
• DOI: 10.1038/nsmb.1765

The protein VP35 from Ebola virus contributes to immune evasion by antagonizing interferon signaling pathways. Now the crystal structure of the interferon inhibitory domain of VP35 bound to dsRNA indicates that VP35 sequesters the dsRNA ends, preventing them from being sensed by RIG-I-like receptors and inhibiting immune responses.
Ebola viral protein 35 (VP35), encoded by the highly pathogenic Ebola virus, facilitates host immune evasion by antagonizing antiviral signaling pathways, including those initiated by RIG-I–like receptors. Here we report the crystal structure of the Ebola VP35 interferon inhibitory domain (IID) bound to short double-stranded RNA (dsRNA), which together with
in vivo
results reveals how VP35-dsRNA interactions contribute to immune evasion. Conserved basic residues in VP35 IID recognize the dsRNA backbone, whereas the dsRNA blunt ends are 'end-capped' by a pocket of hydrophobic residues that mimic RIG-I–like receptor recognition of blunt-end dsRNA. Residues critical for RNA binding are also important for interferon inhibition
in vivo
but not for viral polymerase cofactor function of VP35. These results suggest that simultaneous recognition of dsRNA backbone and blunt ends provides a mechanism by which Ebola VP35 antagonizes host dsRNA sensors and immune responses.