title: Host response to polyomavirus infection is modulated by RNA adenosine deaminase ADAR1 but not by ADAR2.
abstract: Adenosine deaminases acting on RNA (ADARs) catalyze the C-6 deamination of adenosine (A) to produce inosine (I), which behaves as guanine (G), thereby altering base pairing in RNAs with double-stranded character. Two genes, adar1 and adar2, are known to encode enzymatically active ADARs in mammalian cells. Furthermore, two size forms of ADAR1 are expressed by alternative promoter usage, a short (p110) nuclear form that is constitutively made and a long (p150) form that is interferon inducible and present in both the cytoplasm and nucleus. ADAR2 is also a constitutively expressed nuclear protein. Extensive A-to-G substitution has been described in mouse polyomavirus (PyV) RNA isolated late times after infection, suggesting modification by ADAR. To test the role of ADAR in PyV infection, we used genetically null mouse embryo fibroblast cells deficient in either ADAR1 or ADAR2. The single-cycle yields and growth kinetics of PyV were comparable between adar1(-/-) and adar2(-/-) genetic null fibroblast cells. While large T antigen was expressed to higher levels in adar1(-/-) cells than adar2(-/-) cells, less difference was seen in VP1 protein expression levels between the two knockout MEFs. However, virus-induced cell killing was greatly enhanced in PyV-infected adar1(-/-) cells compared to that of adar2(-/-) cells. Complementation with p110 protected cells from PyV-induced cytotoxicity. UV-irradiated PyV did not display any enhanced cytopathic effect in adar1(-/-) cells. Reovirus and vesicular stomatitis virus single-cycle yields were comparable between adar1(-/-) and adar2(-/-) cells, and neither reovirus nor VSV showed enhanced cytotoxicity in adar1(-/-)-infected cells. These results suggest that ADAR1 plays a virus-selective role in the host response to infection.
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, CA 93106, USA.
authors.forename: Cyril X
authors.initials: CX
authors.lastname: George
authors.forename: Charles E
authors.initials: CE
authors.lastname: Samuel
mesh_terms: D000243:Adenosine Deaminase / Q000235:genetics / Q000378:metabolism*; D019943:Amino Acid Substitution; D000818:Animals; D030801:Animals, Genetically Modified; D000952:Antigens, Polyomavirus Transforming / Q000096:biosynthesis / Q000235:genetics; D020029:Base Pairing; D036022:Capsid Proteins / Q000096:biosynthesis / Q000235:genetics; D002460:Cell Line; D003588:Cytopathogenic Effect, Viral; D005347:Fibroblasts; D051379:Mice; D016133:Polymerase Chain Reaction; D011120:Polyomavirus / Q000254:growth & development* / Q000472:pathogenicity; D027601:Polyomavirus Infections / Q000821:virology*; D016601:RNA-Binding Proteins; D012087:Reoviridae / Q000254:growth & development; D018116:Vesiculovirus / Q000254:growth & development
chemical_list: D000952:Antigens, Polyomavirus Transforming; D036022:Capsid Proteins; D016601:RNA-Binding Proteins; C062481:VP1 protein, polyomavirus; C567955:ADARB1 protein, human; D000243:Adenosine Deaminase