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Peer-reviewedCC BYNature Immunology

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

  • Natália G. Sampaio1,2,3
  • Tanja Davis4
  • Linden J. Gearing5,6
  • Antônio Gregorio Dias4
  • Lise Chauveau7
  • Georgie Wray‐McCann5,6
  • Valerie Odon4
  • Vladyslava Liudkovska8
  • Alexandra L. McAllan5,6
  • Chiara Cursi4
  • Alice Mayer4
  • Madara Ratnadiwakara9,6
4 more authors
  • Minna‐Liisa Änkö9,6,10
  • Maciej Cieśla8
  • Paul J. Hertzog5,6
  • Jan Rehwinkel4
10 affiliations
  1. 1Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia. [email protected]
  2. 2Department of Molecular and Translational Sciences, School of Clinical Sciences, Monash University, Clayton, Victoria, Australia. [email protected]
  3. 3Medical Research Council Translational Immune Discovery Unit, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK. [email protected]
  4. 4Medical Research Council Translational Immune Discovery Unit, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
  5. 5Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia
  6. 6Department of Molecular and Translational Sciences, School of Clinical Sciences, Monash University, Clayton, Victoria, Australia
  7. 7RNA viruses and metabolism team, Institut de Recherche en Infectiologie de Montpellier (IRIM), CNRS, University of Montpellier, Montpellier, France
  8. 8IMol Polish Academy of Sciences, Warsaw, Poland
  9. 9Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia
  10. 10Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland
Open at sourceDOICite

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.

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Cite

BibTeXRIS
BibTeX
@article{sampaio2026loss,
  title = {{Loss of cellular RNA homeostasis contributes to MDA5 activation during virus infection}},
  author = {Natália G. Sampaio and Tanja Davis and Linden J. Gearing and Antônio Gregorio Dias and Lise Chauveau and Georgie Wray‐McCann and Valerie Odon and Vladyslava Liudkovska and Alexandra L. McAllan and Chiara Cursi and Alice Mayer and Madara Ratnadiwakara and Minna‐Liisa Änkö and Maciej Cieśla and Paul J. Hertzog and Jan Rehwinkel},
  journal = {Nature Immunology},
  year = {2026},
  month = aug,
  doi = {10.1038/s41590-026-02614-3},
  url = {https://hal.science/hal-05778159v1},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Loss of cellular RNA homeostasis contributes to MDA5 activation during virus infection
AU  - Natália G. Sampaio
AU  - Tanja Davis
AU  - Linden J. Gearing
AU  - Antônio Gregorio Dias
AU  - Lise Chauveau
AU  - Georgie Wray‐McCann
AU  - Valerie Odon
AU  - Vladyslava Liudkovska
AU  - Alexandra L. McAllan
AU  - Chiara Cursi
AU  - Alice Mayer
AU  - Madara Ratnadiwakara
AU  - Minna‐Liisa Änkö
AU  - Maciej Cieśla
AU  - Paul J. Hertzog
AU  - Jan Rehwinkel
PY  - 2026
DA  - 2026/08/11
JO  - Nature Immunology
DO  - 10.1038/s41590-026-02614-3
UR  - https://hal.science/hal-05778159v1
AB  - 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.
SN  - 1529-2908
SN  - 1529-2916
ER  -