title: 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.
authors.affiliation: Department of Biochemistry.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Grieves
authors.affiliation: Department of Biochemistry.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Fye
authors.affiliation: Department of Biochemistry.
authors.forename: Scott
authors.initials: S
authors.lastname: Harvey
authors.affiliation: Department of Microbiology and Immunology, and.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Grayson
authors.affiliation: Department of Biochemistry, Center for Structural Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157 fperrino@wakehealth.edu thollis@wakehealth.edu.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hollis
authors.affiliation: Department of Biochemistry, Center for Structural Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157 fperrino@wakehealth.edu thollis@wakehealth.edu.
authors.forename: Fred W
authors.initials: FW
authors.lastname: Perrino
mesh_terms: D000483:Alleles; D000818:Animals; D000906:Antibodies / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology; D001483:Base Sequence; D002647:Chilblains / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D004247:DNA / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D005090:Exodeoxyribonucleases / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D008178:Lupus Erythematosus, Cutaneous / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009690:Nucleic Acid Conformation; D010641:Phenotype; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics*; D014176:Protein Biosynthesis
chemical_list: D000906:Antibodies; D010750:Phosphoproteins; D004247:DNA; D005090:Exodeoxyribonucleases; C429526:three prime repair exonuclease 1
keywords: DNA; TREX1; autoimmunity; lupus; structure
references.citation: Arthritis Res Ther. 2011;13(5):241
references.pmid: 21989039
references.citation: Nucleic Acids Res. 2012 Sep;40(16):8144-54
references.pmid: 22718982
references.citation: Science. 2013 Feb 15;339(6121):786-91
references.pmid: 23258413
references.citation: J Biol Chem. 2013 Oct 4;288(40):28881-92
references.pmid: 23979357
references.citation: J Immunol. 2013 Dec 15;191(12):6128-35
references.pmid: 24218451
references.citation: Cell Rep. 2014 Jan 16;6(1):1-8
references.pmid: 24388753
references.citation: J Biol Chem. 2014 Apr 18;289(16):11556-65
references.pmid: 24616097
references.citation: Nat Immunol. 2014 May;15(5):415-22
references.pmid: 24747712
references.citation: DNA Repair (Amst). 2014 Jul;19:95-107
references.pmid: 24754999
references.citation: J Immunol. 2014 Jun 15;192(12):5993-7
references.pmid: 24813208
references.citation: JAMA Dermatol. 2015 Apr;151(4):426-31
references.pmid: 25517357
references.citation: J Biol Chem. 2001 May 4;276(18):14718-27
references.pmid: 11278605
references.citation: J Biol Chem. 2001 May 18;276(20):17022-9
references.pmid: 11279105
references.citation: Mol Cell Biol. 2004 Aug;24(15):6719-27
references.pmid: 15254239
references.citation: J Biol Chem. 1969 Sep 25;244(18):5014-9
references.pmid: 5824576
references.citation: J Biol Chem. 1994 Jun 10;269(23):16357-63
references.pmid: 8206943
references.citation: EMBO J. 1999 Jul 1;18(13):3868-75
references.pmid: 10393201
references.citation: J Biol Chem. 1999 Jul 9;274(28):19655-60
references.pmid: 10391904
references.citation: Cell Biochem Biophys. 1999;30(3):331-52
references.pmid: 10403055
references.citation: Mol Cell. 2006 Jul 7;23(1):133-42
references.pmid: 16818237
references.citation: Nat Genet. 2006 Aug;38(8):917-20
references.pmid: 16845398
references.citation: Am J Hum Genet. 2006 Oct;79(4):731-7
references.pmid: 16960810
references.citation: J Biol Chem. 2007 Apr 6;282(14):10537-43
references.pmid: 17293595
references.citation: J Mol Med (Berl). 2007 May;85(5):531-7
references.pmid: 17440703
references.citation: Nat Genet. 2007 Sep;39(9):1065-7
references.pmid: 17660818
references.citation: Nat Genet. 2007 Sep;39(9):1068-70
references.pmid: 17660820
references.citation: Am J Hum Genet. 2007 Oct;81(4):713-25
references.pmid: 17846997
references.citation: Cell. 2007 Nov 30;131(5):873-86
references.pmid: 18045533
references.citation: Cell. 2008 Aug 22;134(4):587-98
references.pmid: 18724932
references.citation: Cell. 2008 Oct 3;135(1):97-109
references.pmid: 18854158
references.citation: J Biol Chem. 2008 Nov 14;283(46):31649-56
references.pmid: 18805785
references.citation: Biochem Soc Trans. 2009 Jun;37(Pt 3):535-8
references.pmid: 19442247
references.citation: Hum Mol Genet. 2009 Oct 15;18(R2):R130-6
references.pmid: 19808788
references.citation: Vet Pathol. 2010 Jul;47(4):664-76
references.pmid: 20448279
references.citation: Ann Rheum Dis. 2010 Oct;69(10):1886-7
references.pmid: 19875384
references.citation: Nat Immunol. 2010 Nov;11(11):1005-13
references.pmid: 20871604
references.citation: J Biomed Biotechnol. 2011;2011:271694
references.pmid: 21403825
references.citation: Cell. 2011 Apr 15;145(2):198-211
references.pmid: 21496641
references.citation: Genes Immun. 2011 Jun;12(4):270-9
references.pmid: 21270825
references.citation: J Biol Chem. 2011 Sep 16;286(37):32373-82
references.pmid: 21808053
references.citation: J Biol Chem. 2011 Nov 18;286(46):40246-54
references.pmid: 21937424
references.citation: DNA Repair (Amst). 2012 Jan 2;11(1):65-73
references.pmid: 22071149
references.citation: Immunity. 2012 Jan 27;36(1):120-31
references.pmid: 22284419