Genome Replication Is Associated With Release of Immunogenic DNA Waste
Innate DNA sensors detect foreign and endogenous DNA to induce responses to infection and cellular stress or damage. Inappropriate activation by self-DNA triggers severe autoinflammatory conditions, including Aicardi-Goutières syndrome (AGS) that can be caused by defects of the cytosolic DNase 3’rep...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-05-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.880413/full |
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| author | Nadja Schubert Tina Schumann Elena Daum Karolin Flade Yan Ge Lara Hagedorn Winfried Edelmann Luise Müller Marc Schmitz Marc Schmitz Marc Schmitz Gunnar Kuut Veit Hornung Rayk Behrendt Rayk Behrendt Axel Roers Axel Roers |
| author_facet | Nadja Schubert Tina Schumann Elena Daum Karolin Flade Yan Ge Lara Hagedorn Winfried Edelmann Luise Müller Marc Schmitz Marc Schmitz Marc Schmitz Gunnar Kuut Veit Hornung Rayk Behrendt Rayk Behrendt Axel Roers Axel Roers |
| author_sort | Nadja Schubert |
| collection | DOAJ |
| description | Innate DNA sensors detect foreign and endogenous DNA to induce responses to infection and cellular stress or damage. Inappropriate activation by self-DNA triggers severe autoinflammatory conditions, including Aicardi-Goutières syndrome (AGS) that can be caused by defects of the cytosolic DNase 3’repair exonuclease 1 (TREX1). TREX1 loss-of-function alleles are also associated with systemic lupus erythematosus (SLE). Chronic activation of innate antiviral immunity in TREX1-deficient cells depends on the DNA sensor cGAS, implying that accumulating TREX1 DNA substrates cause the inflammatory pathology. Retrotransposon-derived cDNAs were shown to activate cGAS in TREX1-deficient neuronal cells. We addressed other endogenous sources of cGAS ligands in cells lacking TREX1. We find that induced loss of TREX1 in primary cells induces a rapid IFN response that requires ongoing proliferation. The inflammatory phenotype of Trex1-/- mice was partially rescued by additional knock out of exonuclease 1, a multifunctional enzyme providing 5’ flap endonuclease activity for Okazaki fragment processing and postreplicative ribonucleotide excision repair. Our data imply genome replication as a source of DNA waste with pathogenic potential that is efficiently degraded by TREX1. |
| first_indexed | 2024-12-12T04:39:10Z |
| format | Article |
| id | doaj.art-d0c9705d51ca42bdb9c763b7317983dc |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-12T04:39:10Z |
| publishDate | 2022-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-d0c9705d51ca42bdb9c763b7317983dc2022-12-22T00:37:52ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-05-011310.3389/fimmu.2022.880413880413Genome Replication Is Associated With Release of Immunogenic DNA WasteNadja Schubert0Tina Schumann1Elena Daum2Karolin Flade3Yan Ge4Lara Hagedorn5Winfried Edelmann6Luise Müller7Marc Schmitz8Marc Schmitz9Marc Schmitz10Gunnar Kuut11Veit Hornung12Rayk Behrendt13Rayk Behrendt14Axel Roers15Axel Roers16Institute for Immunology, Medical Faculty Carl Gustav Carus, University of Technology (TU) Dresden, Dresden, GermanyInstitute for Immunology, Medical Faculty Carl Gustav Carus, University of Technology (TU) Dresden, Dresden, GermanyInstitute for Immunology, Medical Faculty Carl Gustav Carus, University of Technology (TU) Dresden, Dresden, GermanyInstitute for Immunology, Medical Faculty Carl Gustav Carus, University of Technology (TU) Dresden, Dresden, GermanyInstitute for Immunology, Medical Faculty Carl Gustav Carus, University of Technology (TU) Dresden, Dresden, GermanyInstitute for Immunology, Medical Faculty Carl Gustav Carus, University of Technology (TU) Dresden, Dresden, GermanyDepartment of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, United StatesInstitute for Immunology, Medical Faculty Carl Gustav Carus, University of Technology (TU) Dresden, Dresden, GermanyInstitute for Immunology, Medical Faculty Carl Gustav Carus, University of Technology (TU) Dresden, Dresden, GermanyNational Center for Tumor Diseases (NCT), University Hospital Carl Gustav Carus, University of Technology (TU) Dresden, Dresden, GermanyGerman Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, GermanyGene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, GermanyGene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, GermanyInstitute for Immunology, Medical Faculty Carl Gustav Carus, University of Technology (TU) Dresden, Dresden, GermanyInstitute for Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, GermanyInstitute for Immunology, Medical Faculty Carl Gustav Carus, University of Technology (TU) Dresden, Dresden, GermanyInstitute for Immunology, University Hospital Heidelberg, Heidelberg, GermanyInnate DNA sensors detect foreign and endogenous DNA to induce responses to infection and cellular stress or damage. Inappropriate activation by self-DNA triggers severe autoinflammatory conditions, including Aicardi-Goutières syndrome (AGS) that can be caused by defects of the cytosolic DNase 3’repair exonuclease 1 (TREX1). TREX1 loss-of-function alleles are also associated with systemic lupus erythematosus (SLE). Chronic activation of innate antiviral immunity in TREX1-deficient cells depends on the DNA sensor cGAS, implying that accumulating TREX1 DNA substrates cause the inflammatory pathology. Retrotransposon-derived cDNAs were shown to activate cGAS in TREX1-deficient neuronal cells. We addressed other endogenous sources of cGAS ligands in cells lacking TREX1. We find that induced loss of TREX1 in primary cells induces a rapid IFN response that requires ongoing proliferation. The inflammatory phenotype of Trex1-/- mice was partially rescued by additional knock out of exonuclease 1, a multifunctional enzyme providing 5’ flap endonuclease activity for Okazaki fragment processing and postreplicative ribonucleotide excision repair. Our data imply genome replication as a source of DNA waste with pathogenic potential that is efficiently degraded by TREX1.https://www.frontiersin.org/articles/10.3389/fimmu.2022.880413/fullTrex1type I interferonExo1replicationcytosolic DNAinterferonopathy |
| spellingShingle | Nadja Schubert Tina Schumann Elena Daum Karolin Flade Yan Ge Lara Hagedorn Winfried Edelmann Luise Müller Marc Schmitz Marc Schmitz Marc Schmitz Gunnar Kuut Veit Hornung Rayk Behrendt Rayk Behrendt Axel Roers Axel Roers Genome Replication Is Associated With Release of Immunogenic DNA Waste Frontiers in Immunology Trex1 type I interferon Exo1 replication cytosolic DNA interferonopathy |
| title | Genome Replication Is Associated With Release of Immunogenic DNA Waste |
| title_full | Genome Replication Is Associated With Release of Immunogenic DNA Waste |
| title_fullStr | Genome Replication Is Associated With Release of Immunogenic DNA Waste |
| title_full_unstemmed | Genome Replication Is Associated With Release of Immunogenic DNA Waste |
| title_short | Genome Replication Is Associated With Release of Immunogenic DNA Waste |
| title_sort | genome replication is associated with release of immunogenic dna waste |
| topic | Trex1 type I interferon Exo1 replication cytosolic DNA interferonopathy |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.880413/full |
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