Deficiency of adenosine deaminase 2 (DADA2) is a severe, congenital syndrome, which manifests with hematologic, immunologic and inflammatory pathologies. DADA2 is caused by biallelic mutations in ADA2, but the function of ADA2, and the mechanistic link between ADA2 deficiency and the severe inflammatory phenotype remains unclear. Here, 5 we show that monocyte-derived proteomes from DADA2 patients are highly enriched in interferon response proteins. Using immunohistochemistry and detailed glycan analysis we demonstrate that ADA2 is post-translationally modified for sorting to the lysosomes. At acidic, lysosomal pH, ADA2 acts as a novel DNase that degrades cGAS/Sting-activating ligands. Furthermore, we define a clear structure-function relationship for this acidic