Dnase2a Deficiency Uncovers Lysosomal Clearance of Damaged Nuclear DNA via Autophagy

Summary: Deficiencies in DNA-degrading nucleases lead to accumulation of self DNA and induction of autoimmunity in mice and in monogenic and polygenic human diseases. However, the sources of DNA and the mechanisms that trigger immunity remain unclear. We analyzed mice deficient for the lysosomal nuclease Dnase2a and observed elevated levels of undegraded DNA in both phagocytic and nonphagocytic cells. In nonphagocytic cells, the excess DNA originated from damaged DNA in the nucleus based on colocalization studies, live-cell imaging, and exacerbation by DNA-damaging agents. Removal of damaged DNA by Dnase2a required nuclear export and autophagy-mediated delivery of the DNA to lysosomes. Finally, DNA was found to accumulate in Dnase2a−/− or autophagy-deficient cells and induce inflammation via the Sting cytosolic DNA-sensing pathway. Our results reveal a cell-autonomous process for removal of damaged nuclear DNA with implications for conditions with elevated DNA damage, such as inflammation, cancer, and chemotherapy. : Deficiencies in DNA nucleases can lead to the accumulation of self DNA, activation of innate immunity, and development of autoimmune disease. The source of immunostimulatory DNA is not known in most cases. Lan et al. now find that damaged nuclear DNA accumulates outside the nucleus and stimulates Sting-dependent DNA-sensing when mice lack a lysosomal nuclease, Dnase2a. The results support a model in which damaged chromosomal DNA is normally exported from the nucleus and cleared by autophagy