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ADAR1, inosine and the immune sensing system: distinguishing self from non‐self

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The conversion of genomically encoded adenosine to inosine in dsRNA is termed as A‐to‐I RNA editing. This process is catalyzed by two of the three mammalian ADAR proteins (ADAR1 and ADAR2) both of which have essential functions for normal organismal homeostasis. The phenotype of ADAR2 deficiency can be primarily ascribed to a lack of site‐selective editing of a single transcript in the brain. In contrast, the biology and substrates responsible for the Adar1−/− phenotype have remained more elusive. Several recent studies have identified that a feature of absence or reductions of ADAR1 activity, conserved across human and mouse models, is a profound activation of interferon‐stimulated gene signatures and innate immune responses. Further analysis of this observation has lead to the conclusion that editing by ADAR1 is required to prevent activation of the cytosolic innate immune system, primarily focused on the dsRNA sensor MDA5 and leading to downstream signaling via MAVS. The delineation of this mechanism places ADAR1 at the interface between the cells ability to differentiate self‐ from non‐self dsRNA. Based on MDA5 dsRNA recognition requisites, the mechanism indicates that the type of dsRNA must fulfil a particular structural characteristic, rather than a sequence‐specific requirement. While additional studies are required to molecularly verify the genetic model, the observations to date collectively identify A‐to‐I editing by ADAR1 as a key modifier of the cellular response to endogenous dsRNA. WIREs RNA 2016, 7:157–172. doi: 10.1002/wrna.1322 This article is categorized under: RNA Processing > RNA Editing and Modification
Timeline of ADAR1 biology linked to innate immune signaling.
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A coordinated transcriptional response to a lack of ADAR1 editing activity. The 50 most differentially expressed transcripts in Adar1E861A/E861A are compared to WT whole fetal liver (normalized read count for WT and E861A and Log2FC, color coded as indicated by the scale). The expression level of the individual IRF transcriptional factors is provided, all except IRF3 are statistically significantly induced. Many of these transcripts are very lowly or not detectable in ADAR1 editing proficient cells.
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Model of the role of ADAR1 in the response to endogenous dsRNA. Model representation of the innate immune sensing pathway. Individual proteins are color‐coded based on the Log2FC in mRNA expression between Adar1E861A/E861A compared to WT whole fetal liver as indicated in the scale at the bottom of the figure (expression data from GSE58917). (1) Endogenous dsRNA can be edited by ADAR1 (p110 or possibly p150) in the nucleus which would prevent it being a candidate substrate for innate immune sensing if it were to be exported to the cytosol; In the event that an un‐edited endogenous dsRNA was present in the cytosol, (2) ADAR1p150 could edit it and thus render it an unsuitable substrate for MDA5 (3) (and most likely RIG‐I), or bind the dsRNA and prevent sensing by the innate immune system (4) in a manner that does not require editing activity (such a role may account for the extended survival of the Adar1E861A/E861A compared to Adar1/− embryos), or ADAR1p150 neither edits nor binds the dsRNA and it is sensed and bound by MDA5, (5) TLR3 can also sense dsRNA in the endosome; however, this pathway does not appear to be transcriptional activated in the Adar1E861A/E861A cells. Binding of the dsRNA by MDA5 triggers activation of the innate immune signaling cascade and signals via MAVS to activate IRF transcription factors. These translocate to the nucleus and activate transcription (6) of a range of transcripts that participate in the innate immune response. The production of interferon proteins leads to activation of cell surface IFN receptors, (7) which further amplifies the cellular transcriptional response.
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