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.
© 2015 Wiley Periodicals, Inc.