Homologous 2',5'-phosphodiesterases from disparate RNA viruses antagonize antiviral innate immunity.

Zhang R, Jha BK, Ogden KM, Dong B, Zhao L, Elliott R, Patton JT, Silverman RH, Weiss SR
Proc Natl Acad Sci U S A. 2013 110 (32): 13114-9

PMID: 23878220 · PMCID: PMC3740845 · DOI:10.1073/pnas.1306917110

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.

MeSH Terms (26)

2',5'-Oligoadenylate Synthetase Adenine Nucleotides Amino Acid Sequence Animals Binding Sites Capsid Proteins Cell Line Cells, Cultured Endoribonucleases Host-Pathogen Interactions Humans Immunity, Innate Immunoblotting Macrophages Mice Mice, Knockout Molecular Sequence Data Murine hepatitis virus Mutation Oligoribonucleotides Phosphoric Diester Hydrolases RNA Viruses RNA Virus Infections Rotavirus Sequence Homology, Amino Acid Viral Nonstructural Proteins

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