Abstract
RNA editing, particularly A-to-I RNA editing, has been shown to play an essential role in mammalian embryonic development and tissue homeostasis, and is implicated in the pathogenesis of many diseases including skin pigmentation disorder, autoimmune and inflammatory tissue injury, neuron degeneration, and various malignancies. A-to-I RNA editing is carried out by a small group of enzymes, the adenosine deaminase acting on RNAs (ADARs). Only three members of this protein family, ADAR1–3, exist in mammalian cells. ADAR3 is a catalytically null enzyme and the most significant function of ADAR2 was found to be in editing on the neuron receptor GluR-B mRNA. ADAR1, however, has been shown to play more significant roles in biological and pathological conditions. Although there remains much that is not known about how ADAR1 regulates cellular function, recent findings point to regulation of the innate immune response as an important function of ADAR1. Without appropriate RNA editing by ADAR1, endogenous RNA transcripts stimulate cytosolic RNA sensing receptors and therefore activate the IFN-inducing signaling pathways. Overactivation of innate immune pathways can lead to tissue injury and dysfunction. However, obvious gaps in our knowledge persist as to how ADAR1 regulates innate immune responses through RNA editing. Here, we review critical findings from ADAR1 mechanistic studies focusing on its regulatory function in innate immune responses and identify some of the important unanswered questions in the field.
Highlights
Following the pioneering discovery of Dr Bass and colleagues that the conversion of adenosine to inosine was the basis underlying dsRNA-unwinding, and that this conversion was mediated by an adenosine deaminase [1,2], mammalian ADAR1 was first purified from bovine liver nuclear extract [3]
While A-to-I RNA editing could be attributed to ADAR1 and ADAR2 in mammalian cells, no catalytic activity was detected for ADAR3 [12,13,14]
RIG-I deletion did not rescue the lethality of ADAR1−/− embryos, it did not rule out the possibility that ADAR1 regulates RIG-I initiated RNA-sensing signaling in certain pathological conditions
Summary
Following the pioneering discovery of Dr Bass and colleagues that the conversion of adenosine to inosine was the basis underlying dsRNA-unwinding, and that this conversion was mediated by an adenosine deaminase [1,2], mammalian ADAR1 (originally called double-stranded RNA adenosine deaminase, or DRADA) was first purified from bovine liver nuclear extract [3]. ADAR1 plays an indispensable role in embryonic development, since interruption of the ADAR1 allele leads to embryonic lethality with obvious defects in liver hematopoiesis and cell death [46,47,48] This critical function for ADAR1 was demonstrated in knockout animal models more than a decade ago, the delineation of the mechanism by which it functions turned out to be challenging. In addition to its role in editing mRNA and microRNA precursors [25,38,47,49], ADAR1 has been shown to have editing-independent activities [26,50,51], participate in protein complex formation [25,52], and regulate RNA stability and translation efficiency [53,54,55]. RNA activates cytosolic RNA sensing signaling pathways, upregulates IFN production, and elicits innate immune responses
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