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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\u2032,5\u2032-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\u2013mediated degradation. Thus, VP3-CTD is a 2\u2032,5\u2032-PDE able to functionally substitute for ns2 in MHV infection. Remarkably, therefore, two disparate RNA viruses encode proteins with homologous 2\u2032,5\u2032-PDEs that antagonize activation of innate immunity.<\/jats:p>","DOI":"10.1073\/pnas.1306917110","type":"journal-article","created":{"date-parts":[[2013,7,22]],"date-time":"2013-07-22T23:53:19Z","timestamp":1374537199000},"page":"13114-13119","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":131,"title":["Homologous 2\u2032,5\u2032-phosphodiesterases from disparate RNA viruses antagonize antiviral innate immunity"],"prefix":"10.1073","volume":"110","author":[{"given":"Rong","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;"},{"name":"Department of Swine Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, China;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Babal K.","family":"Jha","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristen M.","family":"Ogden","sequence":"additional","affiliation":[{"name":"Rotavirus Molecular Biology Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beihua","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruth","family":"Elliott","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John T.","family":"Patton","sequence":"additional","affiliation":[{"name":"Rotavirus Molecular Biology Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert H.","family":"Silverman","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan R.","family":"Weiss","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2013,7,22]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01471-07"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.8.4133"},{"key":"e_1_3_3_3_2","first-page":"85","volume-title":"Coronavirus Pathogenesis. 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