Figure. Canonical and noncanonical role of ADAR1 (adenosine deaminase acting on RNA 1), in mediating autoinflammatory cardiomyopathy.

A, left, In the normal heart, endogenous RNA is recognized as “self” by ADAR1 mediated A-to-I editing. Thus, “self” dsRNA is not “sensed” by canonical pathways associated with the RNA sensor, MDA5 (melanoma differentiation-associated protein 5) to trigger immune activation via IRF7 (interferon regulatory factor 7) and interferon stress responsive (ISF) gene activation. A, right, ADAR1-deficient cardiomyocytes activate both canonical (via MDA5) and noncanonical pathways (undetermined) to trigger autoimmune cardiomyopathy/myocarditis and premature death in mice. B, Noncanonical pathways of ADAR1 were identified when loss of Ifih1 (gene coding for MDA5) and loss of Irf7 (gene coding for IRF7) could only partially rescue/attenuate the autoimmune cardiomyopathy/myocarditis and premature death in cardiomyocyte-specific ADAR1-deficient mice, resulting in late-onset cardiomyopathy. C, Canonical pathways of ADAR1 were identified when mice expressing a catalytically inactive ADAR1 (disrupted RNA editing functions) and loss of Ifih1 (gene coding for MDA5) resulted in the absence (full rescue) of autoimmune cardiomyopathy/myocarditis and premature death.