Loss of cellular RNA homeostasis contributes to MDA5 activation during virus infection
Year: 2026
Type: article
Abstract: MDA5 is an innate immune RNA sensor that senses infection with a range of viruses and other pathogens. MDA5's RNA agonists are not well defined. Here we used single-nucleotide resolution crosslinking and immunoprecipitation (iCLIP) to study its ligands. Of note, 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. Moreover, overexpression of the splicing factor SRSF3 reduced aberrant transcription and abrogated MDA5 activation. Taken together, we propose that MDA5 surveys RNA processing fidelity and can detect infections by sensing perturbations of post-transcriptional events such as splicing.
Source: Nature Immunology
Institutions: Hudson Institute of Medical Research, University of Oxford, MRC Weatherall Institute of Molecular Medicine, Monash University, Medical Research Council, Centre National de la Recherche Scientifique, Université de Montpellier, Institut de Recherche en Infectiologie de Montpellier, Polish Academy of Sciences, Åbo Akademi University
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $12,690
OpenAlex ID: W7202212002