Protein kinase R and the integrated stress response drive immunopathology caused by mutations in the RNA deaminase ADAR1

Adenosine-to-inosine editing of endogenous Z-form RNA by the deaminase ADAR1 prevents spontaneous MAVS-dependent type I interferon responses

“…It is therefore likely that ADAR1 p.Pro193Ala is hypomorphic and does not cause disease when present homozygously. Consistent with this notion, a recent study reported that Adar1 P195A/P195A mice have no phenotype (Maurano et al, 2021). Similarly, we found that Adar1 mZa/mZa mice did not have any gross abnormalities and were fertile.…”

“…These include the transcription factor ATF4, which induces ISR genes. Interestingly, a recent study reported induction of ISR genes in heterozygous Adar1 P195A/p150À mice (Maurano et al, 2021). We observed induction of some ATF4-dependent genes (Harding et al, 2003) in Adar1 mZa/mZa mice, including Asns (1.3-fold), Slc7a5 (1.3-fold), Slc7a11 (1.9-fold), and Mthfd2 (1.7-fold) (Figure S1E).…”

“…This needs to be considered when extrapolating our results to human. The reader is also referred to a recent study reporting mice with a mutation at this proline (Maurano et al, 2021). Increased levels of ISG transcripts that are induced by nucleic acid sensors indicated that neutrophils initiated IFN responses in Adar1 mZa/mZa lungs.…”

The type I interferonopathies: 10 years on

“…Moreover, Samhd1 −/− mice present with a mild interferon signature and no tissue disease at all 104 , in contrast to AGS due to SAMHD1 loss of function. Finally, Adar -mutant mice, which model the most common mutation (p.Pro193Ala) in ADAR1-related AGS, demonstrate kidney and liver dysfunction but no evidence of brain involvement 112 . Why are these mouse phenotypes so different from the human diseases that they model?…”

“…While a set of mutant genotypes associated with an upregulation of interferon signalling clearly exists, a more important question, at least clinically, is the relevance of this interferon upregulation to phenotype, and thus the potential efficacy of anti-interferon therapy (Box 3 ). The convergence of most of the type I interferonopathy genotypes on nucleic acid metabolism and sensing, data from mouse models demonstrating a phenotypic dependence on type I interferon receptor signalling 17 , 112 , 114 , overlap of clinical features (for example, intracranial calcification seen in more than half of mutant genotypes; as well as the induction of stigmata of the type I interferonopathies in the context of treatment with type I interferon, (for example, ref. 115 )) and the diseases related to discrete negative regulation of the type I interferon receptor discussed earlier herein all support a primary role of enhanced interferon signalling in driving disease (Box 4 ).…”