Ebolavirus VP35 is a multifunctional virulence factor

Abstract

Ebola virus (EBOV) is a member of the filoviridae family that causes severe hemorrhagic fever during sporadic outbreaks, and no approved treatments are currently available. The multifunctional EBOV VP35 protein facilitates immune evasion by antagonizing antiviral signaling pathways and is important for viral RNA synthesis. In order to elucidate regulatory mechanisms and to develop countermeasures, we recently solved the structures of the Zaire and Reston EBOV VP35 interferon inhibitory domain (IID) in the free form and of the Zaire EBOV VP35 IID bound to dsRNA. Together with biochemical, cell biological, and virological studies, our structural work revealed that distinct regions within EBOV VP35 IID contribute to virulence through host immune evasion and viral RNA synthesis. Here we summarize our recent structural and functional studies and discuss the potential of multifunctional Ebola VP35 as a therapeutic target.

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Acknowledgements

Work in the authors' laboratories are supported in part by NIH grants (1F32AI084324 to D.W.L., R01AI059536, R56AI089547 and AI057158 (Northeast Biodefense Center-Lipkin) to C.F.B. and R01AI081914 to G.K.A.); MRCE Developmental Grant (U54AI057160-Virgin(PI) to G.K.A.); Roy J. Carver Charitable Trust (09-3271 to G.K.A.). Use of Argonne National Laboratory Structural Biology Center beamlines at the Advanced Photon Source, for structural studies was supported by the U.S. D.O.E. under contract DE-AC02-06CH11357.

Figures and Tables

Figure 1 Viral infection triggers the IFNβ signal transduction pathway of the host innate immune system, activating the antiviral state. Viral RNAs are detected by cytosolic helicases RIG-I/MDA-5, leading to the phosphorylation and nuclear translocation of transcription factor IR F3/7, which stimulates the production of the IFNβ cytokine. IFNβ activates the JAK/STAT pathway and IFN-stimulated response elements (ISREs) or antiviral genes, such as PKR, MHC class I and 2′5′ OAS.

Figure 2 Structure of ZEBOV VP35 IID (PDB: 3FKE). Ribbon representation of Zaire Ebola VP35 IID in two orientations, along with corresponding electrostatic surfaces that reveal the highly conserved nature of the (A) first basic patch and (B) central basic patch.

Figure 3 Crystal structure of ZEBOV VP35 IID bound to dsRNA (PDB: 3L25). (A) Zaire Ebola VP35 IID in complex with dsRNA reveals two binding modes between protein and dsRNA. (B) The “end-cap” formed by residues at the intersubdomain interface mimic blunt end dsRNA recognition by RLRs. (C) Protein-protein interactions observed between different molecules in the crystal structure reveal previously unrecognized dsRNA-independent functions of VP35 IID.

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