title: Homologous 2',5'-phosphodiesterases from disparate RNA viruses antagonize antiviral innate immunity.
abstract: Efficient and productive virus infection often requires viral countermeasures that block innate immunity. The IFN-inducible 2',5'-oligoadenylate (2-5A) synthetases (OASs) and ribonuclease (RNase) L are components of a potent host antiviral pathway. We previously showed that murine coronavirus (MHV) accessory protein ns2, a 2H phosphoesterase superfamily member, is a phosphodiesterase (PDE) that cleaves 2-5A, thereby preventing activation of RNase L. The PDE activity of ns2 is required for MHV replication in macrophages and for hepatitis. Here, we show that group A rotavirus (RVA), an important cause of acute gastroenteritis in children worldwide, encodes a similar PDE. The RVA PDE forms the carboxy-terminal domain of the minor core protein VP3 (VP3-CTD) and shares sequence and predicted structural homology with ns2, including two catalytic HxT/S motifs. Bacterially expressed VP3-CTD exhibited 2',5'-PDE activity, which cleaved 2-5A in vitro. In addition, VP3-CTD expressed transiently in mammalian cells depleted 2-5A levels induced by OAS activation with poly(rI):poly(rC), preventing RNase L activation. In the context of recombinant chimeric MHV expressing inactive ns2, VP3-CTD restored the ability of the virus to replicate efficiently in macrophages or in the livers of infected mice, whereas mutant viruses expressing inactive VP3-CTD (H718A or H798R) were attenuated. In addition, chimeric viruses expressing either active ns2 or VP3-CTD, but not nonfunctional equivalents, were able to protect ribosomal RNA from RNase L-mediated degradation. Thus, VP3-CTD is a 2',5'-PDE able to functionally substitute for ns2 in MHV infection. Remarkably, therefore, two disparate RNA viruses encode proteins with homologous 2',5'-PDEs that antagonize activation of innate immunity.
authors.affiliation: Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Zhang
authors.forename: Babal K
authors.initials: BK
authors.lastname: Jha
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Ogden
authors.forename: Beihua
authors.initials: B
authors.lastname: Dong
authors.forename: Ling
authors.initials: L
authors.lastname: Zhao
authors.forename: Ruth
authors.initials: R
authors.lastname: Elliott
authors.forename: John T
authors.initials: JT
authors.lastname: Patton
authors.forename: Robert H
authors.initials: RH
authors.lastname: Silverman
authors.forename: Susan R
authors.initials: SR
authors.lastname: Weiss
mesh_terms: D015088:2',5'-Oligoadenylate Synthetase / Q000276:immunology / Q000378:metabolism; D000227:Adenine Nucleotides / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000235:genetics / Q000276:immunology; D036022:Capsid Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D004722:Endoribonucleases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D015151:Immunoblotting; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000821:virology; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D006517:Murine hepatitis virus / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D009154:Mutation; D009843:Oligoribonucleotides / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D012327:RNA Virus Infections / Q000276:immunology / Q000821:virology; D012328:RNA Viruses / Q000276:immunology* / Q000378:metabolism / Q000502:physiology; D012401:Rotavirus / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D017386:Sequence Homology, Amino Acid; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D000227:Adenine Nucleotides; D036022:Capsid Proteins; D009843:Oligoribonucleotides; C442546:VP3 protein, Rotavirus; D017361:Viral Nonstructural Proteins; C023505:2',5'-oligoadenylate; D015088:2',5'-Oligoadenylate Synthetase; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease; D010727:Phosphoric Diester Hydrolases
keywords: Nidovirales; RNA capping enzyme; Reoviridae; interferon-stiumulated gene