Protein Kinase PKR and Adenosine Deaminase ADAR1 as RNA Sensors in Innate Antiviral Immunity

Protein kinase PKR is activated by double‐stranded (ds) RNA and affects translation by phosphorylation of protein synthesis initiation factor eIF‐2. Adenosine deaminase acting on RNA (ADAR1) catalyzes the deamination of adenosine (A) to generate inosine (I) in RNA with ds structure. Because I is recognized as G instead of A, A‐to‐I editing leads to destabilization of dsRNA structures and genetic recoding. ADAR1 and PKR are both interferon (IFN) inducible. The roles of PKR and ADAR1 during the replication of representative RNA and DNA viruses, wild‐type and mutant, were assessed. The E3L protein of vaccinia virus, the C protein of measles virus, and the VAI RNA of adenovirus are known to promote virus growth and among cellular proteins implicated as their targets are PKR and ADAR. The effects of PKR and ADAR1 deficiency on virus growth, beta IFN induction, and virus‐induced cell death were assessed. As exemplified by measles virus, PKR functions as an anti‐viral and pro‐apoptotic host factor. By contrast, ADAR1 can function in a pro‐viral and anti‐apoptotic manner. The anti‐apoptotic activities of ADAR1 correlate with the suppression of activation of pro‐apoptotic functions exemplified by PKR and IRF3. An important function for PKR is as an enhancer of beta IFN induction via adaptor IPS‐1 dependent signaling. (Supported by NIAID, NIH).