Exonuclease TREX1 degrades double-stranded DNA to prevent spontaneous lupus-like inflammatory disease

• DOI: 10.1073/pnas.1423804112
• Publication Date: 2015-04-07T02:23:05Z
• Authors: Jessica L. Grieves; Jason M. Fye; Scott Harvey; Jason M. Grayson; Thomas Hollis; Fred W. Perrino
• Keywords: Inflammation; 0303 health sciences; Base Sequence; Molecular Sequence Data; Autoimmunity; DNA; Phosphoproteins; Antibodies; 3. Good health; Chilblains; Mice; 03 medical and health sciences; Exodeoxyribonucleases; Phenotype; Protein Biosynthesis; Mutation; Lupus Erythematosus, Cutaneous; Animals; Humans; Nucleic Acid Conformation; Alleles; DNA Damage

Significance

The TREX1 enzyme degrades DNA, and mutations in the TREX1 gene cause autoimmune diseases. The TREX1 D18N mutation causes a form of lupus called familial chilblain lupus. We solved the structure of TREX1 D18N bound to dsDNA, showing how the enzyme interacts with dsDNA. We also replaced the TREX1 WT gene in mice with the TREX1 D18N mutated gene and showed how this mutation causes a lupus-like disease. Together, the TREX1 D18N–dsDNA structure and the spontaneous disease exhibited in the TREX1 D18N mouse help to define how TREX1 degrades dsDNA to prevent this molecule from acting as an autoantigen in the mouse and, most likely, in humans to promote autoimmune disease.