The role of RNA editing by ADAR1 in prevention of innate immune sensing of self-RNA

The innate immune system is the first line of the cellular defence against invading pathogens. a critical component of this defence is the capacity to discriminate foreign rna molecules, which are distinct from most cellular rnas in structure and/or modifications. however, a series of rare autoimmune/autoinflammatory diseases in humans highlight the propensity for the innate immune sensing system to be activated by endogenous cellular double-stranded rnas (dsrnas), underscoring the fine line between distinguishing self from non-self. the rna editing enzyme adar1 has recently emerged as a key regulator that prevents innate immune pathway activation, principally the cytosolic dsrna sensor mda5, from inducing interferon in response to double-stranded rna structures within endogenous rnas. adenosine-to-inosine rna editing by adar1 is proposed to destabilise duplexes formed from inverted repetitive elements within rnas, which appear to prevent mda5 from sensing these rna as virus-like in the cytoplasm. aberrant activation of these pathways has catastrophic effects at both a cellular and organismal level, contributing to one of the causes of the conditions collectively known as the type i interferonopathies.