The lysosomal catabolism of nucleic acids—critical regulators of the innate immune system

Abstract Lysosomes play a pivotal role in degrading and recycling cellular macromolecules, including nucleic acids. Notably, nucleic acids are critical modulators of the innate immunity sensed in endo-/lysosomes, highlighting the relevance of their rapid and tightly regulated turnover. This review explores the intricate processes governing the uptake routes of nucleic acids into lysosomes, the lysosomal catabolism of DNA and RNA to nucleosides and phosphate, and the export of the degradation products, emphasizing the key enzymes and proteins, regulatory mechanisms, and pathological implications of impaired degradation. We highlight open questions in this process and discuss controversies in the field. We discuss the interdependence of efficient nucleic acid degradation and endo-/lysosomal nucleic acid sensors (Toll-like receptors) and pathological implications in human diseases as a result of impaired nucleic acid degradation, e.g. in genetic deficiency disorders resulting in loss-of-function of critical enzymes. This review integrates current research findings, highlighting the significance of lysosomal nucleic acid catabolism in cellular physiology and its link to disease pathogenesis, and hopefully stimulates research in the field that will finally fully comprehend this complex interplay between lysosomal degradation and immunity.