Loss of cellular RNA homeostasis contributes to MDA5 activation during virus infection

MDA5’s RNA agonists are not well defined. We used single-nucleotide resolution crosslinking and immunoprecipitation (iCLIP) to study its ligands.

Surprisingly, upon infection with SARS-CoV-2 or encephalomyocarditis virus, MDA5 bound overwhelmingly to cellular RNAs. Many binding sites were intronic and proximal to Alu elements and to potentially base-paired structures. Concomitantly, cytoplasmic levels of aberrant transcripts and intron-containing unspliced transcripts increased in infected cells and displayed enrichment of MDA5 iCLIP peaks.