ADAR1 haploinsufficiency and sustained picornaviral RdRp dsRNA synthesis synergize to dysregulate RNA editing and cause multi-system interferonopathy.

ABSTRACT: Sensing of viral double-stranded RNA (dsRNA) by MDA5 triggers abundant but transient interferon-stimulated gene (ISGs) expression. If dsRNA synthesis is made persistent by transgenically expressing a picornaviral RNA-dependent RNA polymerase (RdRp) in mice, lifelong MDA5-MAVS pathway activation and marked, global ISG upregulation result. This confers robust protection from viral diseases, but in contrast to numerous other chronic MDA5 hyperactivation states, the mice suffer no autoimmune or other health consequences. Here, we find that they further confound expectations by being resistant to a strong autoimmunity (lupus) provocation. However, knockout of one allele of Adar breaks the autoinflammation-protected state of RdRp^tg mice and results in a severe disease that rese

SUBMITTER: Miller CM 

PROVIDER: S-EPMC12345148 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature