ArticleProceedings of the National Academy of Sciences of the United States of America2015
Exonuclease TREX1 degrades double-stranded DNA to prevent spontaneous lupus-like inflammatory disease.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 111 papers.
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Who cites it
111 citing papers in PubMed, 177 citations in OpenAlex.
- Selective targeting of human TREX1 exonuclease by small molecule inhibitors is mediated by a conformational switch.NAR molecular medicine · 2026Article
- Rational design of carbazole-based STING inhibitors for treating cGAS-STING pathway-driven inflammatory disorders.Nature communications · 2026Article
- Dysregulation of the DNA repair‑immune axis: Targeted therapeutic strategies for autoimmune diseases (Review).International journal of molecular medicine · 2026Review
- Integrative Analyses Identify a cGAS-STING Pathway-Driven Signature With Context-Dependent Roles in Systemic Lupus Erythematosus.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Trex1 overexpression leads to longer lifespans and fragmented sleep inApplied biological chemistry · 2026Article
- Augmentation of DNA exonuclease TREX1 in macrophages as a therapy for cardiac ischemic injury.Science translational medicine · 2025Article
- PRRs-Dependent and Independent Mechanisms of STING Signaling in Inflammatory and Autoimmune Diseases.Biomedicines · 2025Review
- Activation and regulation of cGAS-STING signaling in cancer cells.Molecular cell · 2025Review
- Mouse models of type I interferonopathies.Human molecular genetics · 2025Review
- Review
- Systemic Sclerosis with Interstitial Lung Disease: Identification of Novel Immunogenetic Markers and Ethnic Specificity in Kazakh Patients.Epidemiologia (Basel, Switzerland) · 2025Article
- Targeting Innate Immune Checkpoint TREX1 Is a Safe and Effective Immunotherapeutic Strategy in Cancer.Cancer research · 2025Article
- Misdirected yet intact TREX1 exonuclease activity causes human cerebral and systemic small vessel disease.Brain : a journal of neurology · 2025Article
- Cryoproteins in Non-HCV-Related Autoimmune Disorders: A Serious Cold-Induced Problem.Diagnostics (Basel, Switzerland) · 2025Review
- Induction of Type I Interferon-Dependent Activation and Migration of Inflammatory Dendritic Cells to Local Lymph Nodes by UV Light Exposure.Arthritis & rheumatology (Hoboken, N.J.) · 2025Article
- Prevalence and impact of molecular variation in the three-prime repair exonuclease 1 TREX1 and its implications for oncology.Human genomics · 2025Article
- AP-1-dependent c-Fos activation by TREX1 drives M2 macrophage polarization and mitigates osteoarthritis progression.Cellular and molecular life sciences : CMLS · 2025Article
- Effect of methyl DNA adducts on 3'-5' exonuclease activity of human TREX1.The Biochemical journal · 2025Article
- Opportunities and limitations of B cell depletion approaches in SLE.Nature reviews. Rheumatology · 2025Review
- Implications of tissue specific STING protein flux and abundance on inflammation and the development of targeted therapeutics.PloS one · 2025Article
51 more citing papers are in PubMed but not listed here.
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.