Journal Article

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

Hollis, Thomas, Grayson, Jason M., Harvey, Scott, Perrino, Fred W., Grieves, Jessica L., Fye, Jason M.

2015

Overview

The TREX1 gene encodes a potent DNA exonuclease, and mutations in TREX1 cause a spectrum of lupus-like autoimmune diseases. Most lupus patients develop autoantibodies to double-stranded DNA (dsDNA), but the source of DNA antigen is unknown. The TREX1 D18N mutation causes a monogenic, cutaneous form of lupus called familial chilblain lupus, and the TREX1 D18N enzyme exhibits dysfunctional dsDNA-degrading activity, providing a link between dsDNA degradation and nucleic acid-mediated autoimmune disease. We determined the structure of the TREX1 D18N protein in complex with dsDNA, revealing how this exonuclease uses a novel DNA-unwinding mechanism to separate the polynucleotide strands for single-stranded DNA (ssDNA) loading into the active site. The TREX1 D18N dsDNA interactions coupled with catalytic deficiency explain how this mutant nuclease prevents dsDNA degradation. We tested the effects of TREX1 D18N in vivo by replacing the TREX1 WT gene in mice with the TREX1 D18N allele. The TREX1 D18N mice exhibit systemic inflammation, lymphoid hyperplasia, vasculitis, and kidney disease. The observed lupus-like inflammatory disease is associated with immune activation, production of autoantibodies to dsDNA, and deposition of immune complexes in the kidney. Thus, dysfunctional dsDNA degradation by TREX1 D18N induces disease in mice that recapitulates many characteristics of human lupus. Failure to clear DNA has long been linked to lupus in humans, and these data point to dsDNA as a key substrate for TREX1 and a major antigen source in mice with dysfunctional TREX1 enzyme. 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.

• Publisher: National Academy of Sciences
• Subject: Alleles / Animals / Antibodies - immunology / Autoimmune diseases / Autoimmunity - immunology / Base Sequence / Biological Sciences / Chilblains - enzymology / Chilblains - genetics / Chilblains - pathology / Deoxyribonucleic acid / DNA / DNA - chemistry / DNA - genetics / DNA - metabolism / DNA Damage / Enzymes / Exodeoxyribonucleases - chemistry / Exodeoxyribonucleases - genetics / Genes / Humans / Immunology and Inflammation / Inflammation - pathology / Kidneys / Lupus / Lupus Erythematosus, Cutaneous - enzymology / Lupus Erythematosus, Cutaneous - genetics / Lupus Erythematosus, Cutaneous - pathology / Mice / Molecular Sequence Data / Mutation / Mutation - genetics / Nucleic Acid Conformation / Nucleic acids / Phenotype / Phosphoproteins - chemistry / Phosphoproteins - genetics / Protein Biosynthesis / Rodents