Lysosomal DNaseII degrades nuclear DNA and prevents self DNA recognition (159.17)

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Abstract The aberrant activation of innate immune sensors by self nucleic acids can foster the development of autoimmunity. For example, the absence of nucleases that degrade self nucleic acids leads to autoimmune diseases in mice and humans. DNaseII is the major lysosomal DNA-degrading nuclease. Its deletion in mice results in the accumulation of self DNA, induction of inflammatory cytokines, and development of chronic polyarthritis that resembles human rheumatoid arthritis. DNaseII is known to degrade extracellular DNA in phagocytes. However, given its ubiquitous expression across cell types, we hypothesized that the nuclease plays a broader role in the clearance of DNA. Supporting this notion, DNA accumulated in both phagocytic and non-phagocytic cells from DNaseII-deficient mice, and could be further elevated by treatment with DNA-damaging agents. Concomitantly, cytokines and other immune genes were upregulated through a Sting-mediated cytosolic nucleic acid sensing pathway. Surprisingly, DNA accumulated within nuclear buds and extranuclear aggregates that often co-localized with autophagic and lysosomal markers. A deficiency in autophagy displayed higher levels of extranuclear DNA and enhanced Sting-dependent innate immune response. The observed nuclear to lysosomal DNA clearance process appears to eliminate discarded nuclear DNA in the steady state and in response to DNA damage, and protect cells and organisms from developing pathological immunity to self DNA.