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

Authors

Natália G Sampaio, Tanja Davis, Linden J Gearing, Antonio G Dias Junior, Lise Chauveau, Georgie Wray-McCann, Valerie Odon, Vladyslava Liudkovska, Alexandra L McAllan, Chiara Cursi, Alice Mayer, Madara Ratnadiwakara, Minna-Liisa Änkö, Maciej Cieśla, Paul J Hertzog, Jan Rehwinkel

Published in

Nature immunology. Aug 11, 2026. Epub Aug 11, 2026.

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.

PMID:
42581186
Bibliographic data and abstract were imported from PubMed on 12 Aug 2026.

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