Genome Replication Is Associated With Release of Immunogenic DNA Waste

Frontiers in Immunology

Winfried Edelmann¹  Veit Hornung²  Gunnar Kuut²  Marc Schmitz³  Rayk Behrendt⁴  Karolin Flade⁵  Nadja Schubert⁵  Tina Schumann⁵  Elena Daum⁵  Lara Hagedorn⁵  Luise Müller⁵  Yan Ge⁵  Axel Roers⁶ 

[1]Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, United States

[2]Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany

[3]German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany

[4]Institute for Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany

[5]Institute for Immunology, Medical Faculty Carl Gustav Carus, University of Technology (TU) Dresden, Dresden, Germany

[6]Institute for Immunology, University Hospital Heidelberg, Heidelberg, Germany

[7]National Center for Tumor Diseases (NCT), University Hospital Carl Gustav Carus, University of Technology (TU) Dresden, Dresden, Germany

关键词: Trex1;    type I interferon;    Exo1;    replication;    cytosolic DNA;    interferonopathy;   

DOI  :  10.3389/fimmu.2022.880413

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown