Loss of epitranscriptomic mitochondrial RNA surveillance drives epithelial type I interferon and inflammation in autoimmunity
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.
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BibTeX
@article{arcohierves2026loss,
title = {{Loss of epitranscriptomic mitochondrial RNA surveillance drives epithelial type I interferon and inflammation in autoimmunity}},
author = {Alejandro Arco-Hierves and Konstantina Pamboukas and Linda Bilonda Mutala and Lukasz Borowski and Celine Mayet and Paul Mazet and Sacha Silva-Saffar and Dory Vergallo and Anna Paszek and Marta Dilling and Laurie Askenatzis and Juliette Pascaud and Philippe Labrot and Charlene Lasgi and Johannes Spelbrink and Albertas Navickas and Thibaut Naninck and Nabila Seddiki and Arnaud Tete and Roman Szczesny and Gaetane Nocturne and Xavier Mariette and Rami Bechara},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2026},
month = aug,
doi = {10.1073/pnas.2534325123},
url = {https://hal.science/hal-05757752v1},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Loss of epitranscriptomic mitochondrial RNA surveillance drives epithelial type I interferon and inflammation in autoimmunity
AU - Alejandro Arco-Hierves
AU - Konstantina Pamboukas
AU - Linda Bilonda Mutala
AU - Lukasz Borowski
AU - Celine Mayet
AU - Paul Mazet
AU - Sacha Silva-Saffar
AU - Dory Vergallo
AU - Anna Paszek
AU - Marta Dilling
AU - Laurie Askenatzis
AU - Juliette Pascaud
AU - Philippe Labrot
AU - Charlene Lasgi
AU - Johannes Spelbrink
AU - Albertas Navickas
AU - Thibaut Naninck
AU - Nabila Seddiki
AU - Arnaud Tete
AU - Roman Szczesny
AU - Gaetane Nocturne
AU - Xavier Mariette
AU - Rami Bechara
PY - 2026
DA - 2026/08/24
JO - Proceedings of the National Academy of Sciences of the United States of America
DO - 10.1073/pnas.2534325123
UR - https://hal.science/hal-05757752v1
AB - 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.
SN - 0027-8424
SN - 1091-6490
ER -