How cells mistake their own mitochondrial RNA for a viral infection in Sjögren’s disease

What is it about?

Sjögren’s disease is an autoimmune disease in which the immune system attacks the glands that produce saliva and tears. A hallmark of the disease is a persistent antiviral-like response called the interferon response, but what triggers it has remained unclear. We discovered that the trigger can come from within the cells themselves. Mitochondria normally produce RNA that is carefully controlled and removed. We found that an RNA-modifying enzyme called METTL3 helps maintain this process by supporting REXO2, an enzyme that clears mitochondrial RNA. When this pathway is impaired, mitochondrial double-stranded RNA accumulates and can escape into the cell. The cell mistakes this RNA for a viral signal and activates an interferon response, even though no virus is present.

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Photo by National Institute of Allergy and Infectious Diseases on Unsplash

Photo by National Institute of Allergy and Infectious Diseases on Unsplash

Why is it important?

Our findings provide a new explanation for how chronic inflammation can begin and persist in Sjögren’s disease without an ongoing viral infection. We found reduced REXO2 in salivary gland epithelial cells from people with Sjögren’s disease, and lower REXO2 was associated with stronger interferon and inflammatory activity. The study reveals an unexpected connection between RNA modification, mitochondria and autoimmunity: cells can generate their own “viral-like” danger signal when mitochondrial RNA surveillance fails. This pathway could provide new biomarkers and therapeutic opportunities for Sjögren’s disease and potentially other autoimmune diseases driven by excessive interferon responses.

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