DNASE1L3 maintains homeostatic levels of mitochondrial DNA on the mammalian cell surface.

Mitochondrial DNA is tethered to the surface of select mammalian cells and is cleared by DNASE1L3, with increased surface DNA linked to autoimmune risk.

• Why it matters: Understanding how extracellular nucleic acids are regulated is crucial for deciphering immune responses and autoimmune disease mechanisms, yet the mechanisms controlling cell surface DNA levels remain unclear.
• What they did: The study used human and murine B cells to show that mitochondrial DNA accumulates on cell surfaces in clusters, partially overlapping with RNA-binding domains, and that DNASE1L3 can clear this DNA.
• The result: Patients with a DNASE1L3 missense variant exhibit increased surface DNA on B and T cells, suggesting that DNASE1L3 deficiency may contribute to autoimmune disease susceptibility.