Exonuclease TREX1 degrades double-stranded DNA to prevent spontaneous lupus-like inflammatory disease
- 6 April 2015
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 112 (16), 5117-5122
- https://doi.org/10.1073/pnas.1423804112
Abstract
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.Keywords
This publication has 46 references indexed in Scilit:
- Autoimmunity Initiates in Nonhematopoietic Cells and Progresses via Lymphocytes in an Interferon-Dependent Autoimmune DiseaseImmunity, 2012
- Defects in DNA degradation revealed in crystal structures of TREX1 exonuclease mutations linked to autoimmune diseaseDNA Repair, 2012
- The TREX1 Exonuclease R114H Mutation in Aicardi-Goutières Syndrome and Lupus Reveals Dimeric Structure Requirements for DNA Degradation ActivityJournal of Biological Chemistry, 2011
- Human Flap Endonuclease Structures, DNA Double-Base Flipping, and a Unified Understanding of the FEN1 SuperfamilyCell, 2011
- Evaluation of the TREX1 gene in a large multi-ancestral lupus cohortGenes & Immunity, 2011
- The cytosolic exonuclease TREX1 inhibits the innate immune response to human immunodeficiency virus type 1Nature Immunology, 2010
- Mre11 Dimers Coordinate DNA End Bridging and Nuclease Processing in Double-Strand-Break RepairCell, 2008
- Trex1 Prevents Cell-Intrinsic Initiation of AutoimmunityCell, 2008
- Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 are associated with systemic lupus erythematosusNature Genetics, 2007
- A mutation in TREX1 that impairs susceptibility to granzyme A-mediated cell death underlies familial chilblain lupusJournal of Molecular Medicine, 2007