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

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.

Restriction of Human Cytomegalovirus Replication by ISG15, a Host Effector Regulated by cGAS-STING Double-Stranded-DNA Sensing

“…Type I interferonopathies, like Aicardi-Gourierres syndrome (AGS) and systemic lupus erythematosus (SLE), are characterized by excessive type I interferon production and result from mutations in a number of genes, including one that limits cytoplasmic dsDNA accumulation, encoding the exonuclease TREX1 (44)(45)(46). Remarkably, autoimmunity associated with TREX1 deficiency is dependent upon cGAS, further indicating a role for dsDNA-sensing disease pathology (47,48). A modified proteome enriched with ISGylated proteins resulting from dsDNA-induced ISG15 accumulation might contribute to disease severity or progression.…”

Cytosolic Nuclease TREX1 Regulates Oligosaccharyltransferase Activity Independent of Nuclease Activity to Suppress Immune Activation

“…A recently published TREX1-D18N knock-in mouse showed DNA-mediated systemic inflammation and lupus-like syndrome similar to Trex1 −/− mice, although with much longer survival (>40 weeks) comparing to Trex1 −/− mice (8–10 weeks) (Grieves et al, 2015). These observations suggest that both DNA- and glycan-mediated immune defects contribute to severe disease in Trex1 −/− mice.…”

The Exonuclease Trex2 Shapes Psoriatic Phenotype

“…Additionally, no dramatic changes were observed in the expression of the ubiquitous nucleases that are required to maintain the steady-state degradation of DNA, including endonuclease DNase I, which is responsible for breaking down extracellular DNA (Napirei et al, 2000), the lysosomal endonuclease DNase II, which is involved in the clearance of engulfed apoptotic nuclei (Kawane et al, 2001;Kawane et al, 2003) and damaged nuclear DNA (Lan et al, 2014), and the exonuclease TREX1, which is implicated in cytoplasmic DNA degradation (Gehrke et al, 2013;Stetson et al, 2008). Deficiencies in these nucleases lead to the accumulation of self DNA, which triggers a strong type I interferon signature and results in autoinflammatory diseases (Gall et al, 2012;Grieves et al, 2015;Yoshida et al, 2005). In contrast, TREX2 deficiency dampened the inflammatory response in a IMQ-induced psoriasis-like mouse model, and in response to ultraviolet-B radiation (Manils et al, 2015).…”

“…Indeed, cytosolic DNA in keratinocytes and extracellular DNA associated with neutrophil extracellular traps are found in psoriatic skin but are not detected in healthy skin (Dombrowski et al, 2011;Lin et al, 2011). It is of note that nucleases are implicated in the free nucleic acid degradation and these have been involved in inflammatory diseases (Grieves et al, 2015;Kawane et al, 2006;Napirei et al, 2000;Yang et al, 2007), but their role in psoriasis still remains undefined. Interestingly, the DNA exonuclease TREX2 is one of the genes that is most highly enriched in psoriatic lesions compared to normal skin (Li et al, 2014).…”