Loss of epitranscriptomic mitochondrial RNA surveillance drives epithelial type I interferon and inflammation in autoimmunity
Year: 2026
Type: article
Abstract: Chronic interferon (IFN) activation is a hallmark of autoimmune diseases such as systemic lupus erythematosus and Sjögren’s disease (SjD), where epithelial cells are key contributors. Although viral and retroelement triggers have been proposed as triggers, direct evidence in patient tissues is limited, and endogenous mechanisms of epithelial IFN dysregulation remain unclear. Mitochondrial double-stranded RNA (mt-dsRNA) is a potent type I IFN (IFN-I) inducer, but its regulation in epithelial cells is poorly understood. We identify a mechanism in which the RNA methyltransferase METTL3 stabilizes REXO2 mRNA in primary salivary gland epithelial cells through N6 -methyladenosine (m 6 A) modification. REXO2 encodes a mitochondrial exonuclease that controls mt-dsRNA. METTL3 inhibition reduces REXO2, causing mt-dsRNA accumulation and IFN-I signaling amplification and inflammation. Single-cell and bulk transcriptomic analyses, together with immunofluorescence of salivary gland tissues from SjD patients and controls, reveal reduced REXO2 expression and elevated IFN-I signatures in SjD. Rexo2 is likewise downregulated in epithelial cells of a spontaneous SjD mouse model. REXO2 loss amplifies IFN-I responses and inflammation across several epithelial contexts, while methyl donors restore REXO2 and dampen IFN activation, highlighting a targetable regulatory checkpoint in IFN-driven autoimmune diseases, alongside potential parallel stress pathways.
Authors: Alejandro Arco-Hierves, Konstantina Pamboukas, Linda Bilonda Mutala, Lukasz S. Borowski, Celine Mayet, Paul Mazet, Sacha E. Silva-Saffar, Dory Vergallo, Anna Paszek, Marta M. Dilling, Laurie Askenatzis, Juliette Pascaud, Philippe Labrot, Charlene Lasgi, Johannes N. Spelbrink, Albertas Navickas, Thibaut Naninck, Nabila Seddiki, Arnaud Tete, Roman J. Szczesny, Gaetane Nocturne, Xavier Mariette, Rami Bechara
Institutions: Inserm, Commissariat à l'Énergie Atomique et aux Énergies Alternatives, Université Paris-Saclay, CEA Paris-Saclay, Infectious Disease Models and Innovative Therapies, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, University of Warsaw, Radboud University Medical Center, Centre National de la Recherche Scientifique, Centre Hospitalier Universitaire de Nantes, UMS BioCore, Structure Fédérative de Recherche Bonamy, Nantes Université, Institut Curie, Intégrité du génome, ARN et cancer, UNSW Sydney, Kirby Institute, Université Paris Cité, Health and Functional Exposomics, Assistance Publique – Hôpitaux de Paris, Bicêtre Hospital
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: hybrid
OpenAlex ID: W7204127755