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ADAR1, an interferon inducible adenosine deaminase acting on RNA, catalyzes the C6 deamination of adenosine (A) to produce inosine (I) in RNA with double-stranded (ds) character, leading to genetic recoding and altered RNA structure as I pairs as G instead of A. Adar1 expression occurs from multiple promoters and encodes an IFN-inducible p150 cytoplasmic protein and a constitutively expressed N-terminally truncated p110 nuclear protein. The roles of ADAR1 p150 and p110 in uninfected and virus-infected cells were examined using human cell clones stably deficient in ADAR1, mouse cells genetically deficient in ADAR1, and by complementation strategies. Exemplified by measles virus (MV) infected cells, ADAR1 suppressed activation of PKR and IRF3, suppressed IFN β induction, and protected cells from stress granule formation and cytopathic damage. RNA expression profiles and A-to-I editing were characterized by qPCR and RNA deep sequencing, with differences found between CKO mutant and parental MV infections, and between untreated and IFN-treated uninfected cells. Both non-self (viral) and self (cellular) RNAs with ds character were identified and their editing characterized. Results obtained with mouse cells genetically deficient in either adar1 or the related deaminase adar2, or stat1 or stat2, suggest a central role of ADAR1 in overall A-to-I editing and p150 in the IFN-induced editing and innate immunity RNA sensing. In summary, ADAR1 behaved as an anti-apoptotic host factor that suppressed innate immune activities and was pro-viral. Our findings furthermore implicate a balanced interplay between PKR and ADAR1, two IFN inducible dsRNA binding enzymes, in modulating IFN β protein production and stress responses. |
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