期刊
CELL REPORTS
卷 9, 期 1, 页码 180-192出版社
CELL PRESS
DOI: 10.1016/j.celrep.2014.08.074
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类别
资金
- NIH [DK43351, DK57521]
- NIH Director's New Innovator Award [DP2 OD002230]
- MGH Research Scholars Program
- [T32 DK007540-22]
- [T32 AI060548-04]
- [T32 AI060548-05]
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.
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