Cell https://doi.org/10.1016/j.cell.2017.12.016 (25 January 2018)

Gain-of-function mutations in the gene encoding the dsRNA sensor MDA5 result in enhanced basal signaling in the absence of viral infection. In Cell, Hur and colleagues show that constitutive activation of mutant MDA5 in Aicardi-Goutières syndrome results from loss of tolerance to cellular dsRNA formed by Alu elements. Both wild-type MDA5 and mutant MDA5 require dsRNA-mediated bridging for activation. Alu is a 300-nucleotide interspersed element that constitutes 10% of the genome and can form Alu–Alu duplexes in an inverted-repeat configuration. Among endogenous dsRNAs, Alu–Alu hybrids formed by inverted-repeat Alu activate mutant MDA5, but not wild-type MDA5, probably because wild-type MDA5 is less tolerant of the structural irregularity of Alu–Alu hybrids and their post-transcriptional modification by adenosine deaminase. These observations indicate a delicate balance between recognition of self RNA and activation of innate immunity.