title: TREX1 deficiency triggers cell-autonomous immunity in a cGAS-dependent manner.
abstract: Cytosolic detection of DNA is crucial for the initiation of antiviral immunity but can also cause autoimmunity in the context of endogenous nucleic acids being sensed. Mutations in the human 3' repair exonuclease 1 (TREX1) have been linked to the type I IFN-associated autoimmune disease Aicardi-Goutières syndrome. The exact mechanisms driving unabated type I IFN responses in the absence of TREX1 are only partly understood, but it appears likely that accumulation of endogenous DNA species triggers a cell-autonomous immune response by activating a cytosolic DNA receptor. In this article, we demonstrate that knocking out the DNA sensor cyclic GMP-AMP synthase completely abrogates spontaneous induction of IFN-stimulated genes in TREX1-deficient cells. These findings indicate a key role of cyclic GMP-AMP synthase for the initiation of self-DNA-induced autoimmune disorders, thus providing important implications for novel therapeutic approaches.
authors.affiliation: Institute of Molecular Medicine, University Hospital, University of Bonn, 53127 Bonn, Germany; and.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ablasser
authors.affiliation: Institute of Molecular Medicine, University Hospital, University of Bonn, 53127 Bonn, Germany; and.
authors.forename: Inga
authors.initials: I
authors.lastname: Hemmerling
authors.affiliation: Institute of Molecular Medicine, University Hospital, University of Bonn, 53127 Bonn, Germany; and.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Schmid-Burgk
authors.affiliation: Institute for Immunology, Medical Faculty Carl Gustav Carus, University of Technology, 01307 Dresden, Germany.
authors.forename: Rayk
authors.initials: R
authors.lastname: Behrendt
authors.affiliation: Institute for Immunology, Medical Faculty Carl Gustav Carus, University of Technology, 01307 Dresden, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Roers
authors.affiliation: Institute of Molecular Medicine, University Hospital, University of Bonn, 53127 Bonn, Germany; and veit.hornung@uni-bonn.de.
authors.forename: Veit
authors.initials: V
authors.lastname: Hornung
mesh_terms: D000818:Animals; D020274:Autoimmune Diseases of the Nervous System / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005090:Exodeoxyribonucleases / Q000235:genetics / Q000276:immunology*; D017353:Gene Deletion; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009421:Nervous System Malformations / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D009713:Nucleotidyltransferases / Q000235:genetics / Q000276:immunology*; D010750:Phosphoproteins / Q000235:genetics / Q000276:immunology*; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
chemical_list: D005090:Exodeoxyribonucleases; D009713:Nucleotidyltransferases; D010750:Phosphoproteins; C578390:cGAS protein, human; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase; C578391:cGAS protein, mouse; C429526:three prime repair exonuclease 1