Roles of ADAR1 in IFN-signaling pathway
Date Issued
2012
Date
2012
Author(s)
Chen, Jung-Hung
Abstract
ADAR1 enzyme catalyzes deamination of adenine(A) on double stranded RNA to yield inosine(I). Because inosine is recognized as guanine by cellular machineries, such ADAR1-meidated post-transcriptional nucleotide sequence modification can affect several gene expressions and biological processes. Several studies have demonstrated that, in addition to cellular targets, viral transcripts are substrates for ADAR1, and that ADAR1 exhibits both anti-viral and proviral activities. Interferon (IFN), acting as an antiviral agent, is known to induce the expression of ADAR1 p150 isoform, further suggesting that ADAR1 may be linked to the IFN signaling pathway; however, its roles in this regulation remains uncharacterized. Our recent deep sequencing approach of identifying gene targets of ADAR1 revealed several candidate genes with functions associated with RLR and JAK/STAT signaling. We tested and confirmed editing events and RNA expression level of IFI27L1, IFNAR1, IFNAR2, MAVS, RIG-1 and PRKRA. The A-to-I editing events are confirmed by Sanger sequencing, which further showed obvious ADAR1-dependent editing events in IFI27L1, IFNAR1, IFNAR2, MAVS and RIG-1. Furthermore, higher RNA expression level of IFI27L1 is detected in ADAR1 knockdown cells. With regard to the PRKRA transcript, our observation and sequencing data further imply that there is an anti-sense transcript overlapping with 3’ end of the PRKRA gene locus and that RNA editing may be linked to its regulation. Intriguingly, both mRNA as well as protein expression are decreased and half-life time of the antisense transcript is increased after ADAR1 knockdown. Based on these preliminary findings, we hypothesize that ADAR1 may affect these genes at post-transcriptional level, and in turn modulate the associated signaling pathway. Future work focused on dissecting the mechanism of ADAR1 function in RLR and JAK/STAT signaling as well as in the regulation of PRKRA expression is discussed.
Subjects
ADAR1
RNA editing
antisense transcript
IFN-signaling pathway
Type
thesis
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