title: DNA damage primes the type I interferon system via the cytosolic DNA sensor STING to promote anti-microbial innate immunity.
abstract: Dysfunction in Ataxia-telangiectasia mutated (ATM), a central component of the DNA repair machinery, results in Ataxia Telangiectasia (AT), a cancer-prone disease with a variety of inflammatory manifestations. By analyzing AT patient samples and Atm(-/-) mice, we found that unrepaired DNA lesions induce type I interferons (IFNs), resulting in enhanced anti-viral and anti-bacterial responses in Atm(-/-) mice. Priming of the type I interferon system by DNA damage involved release of DNA into the cytoplasm where it activated the cytosolic DNA sensing STING-mediated pathway, which in turn enhanced responses to innate stimuli by activating the expression of Toll-like receptors, RIG-I-like receptors, cytoplasmic DNA sensors, and their downstream signaling partners. This study provides a potential explanation for the inflammatory phenotype of AT patients and establishes damaged DNA as a cell intrinsic danger signal that primes the innate immune system for a rapid and amplified response to microbial and environmental threats.
authors.affiliation: Laboratory for Molecular Infection Medicine Sweden, Umeå University, 90 187 Umeå, Sweden; Department of Molecular Biology, Umeå University, 90 187 Umeå, Sweden; Umeå Centre for Microbial Research, Umeå University, 90 187 Umeå, Sweden.
authors.forename: Anetta
authors.initials: A
authors.lastname: Härtlova
authors.affiliation: Laboratory for Molecular Infection Medicine Sweden, Umeå University, 90 187 Umeå, Sweden; Department of Molecular Biology, Umeå University, 90 187 Umeå, Sweden; Umeå Centre for Microbial Research, Umeå University, 90 187 Umeå, Sweden.
authors.forename: Saskia F
authors.initials: SF
authors.lastname: Erttmann
authors.affiliation: Laboratory for Molecular Infection Medicine Sweden, Umeå University, 90 187 Umeå, Sweden; Department of Molecular Biology, Umeå University, 90 187 Umeå, Sweden; Umeå Centre for Microbial Research, Umeå University, 90 187 Umeå, Sweden.
authors.forename: Faizal Am
authors.initials: FA
authors.lastname: Raffi
authors.affiliation: Laboratory for Molecular Infection Medicine Sweden, Umeå University, 90 187 Umeå, Sweden; Department of Molecular Biology, Umeå University, 90 187 Umeå, Sweden; Umeå Centre for Microbial Research, Umeå University, 90 187 Umeå, Sweden.
authors.forename: Anja M
authors.initials: AM
authors.lastname: Schmalz
authors.affiliation: Laboratory for Molecular Infection Medicine Sweden, Umeå University, 90 187 Umeå, Sweden; Department of Molecular Biology, Umeå University, 90 187 Umeå, Sweden; Umeå Centre for Microbial Research, Umeå University, 90 187 Umeå, Sweden.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Resch
authors.affiliation: Laboratory for Molecular Infection Medicine Sweden, Umeå University, 90 187 Umeå, Sweden; Department of Molecular Biology, Umeå University, 90 187 Umeå, Sweden; Umeå Centre for Microbial Research, Umeå University, 90 187 Umeå, Sweden.
authors.forename: Sharath
authors.initials: S
authors.lastname: Anugula
authors.affiliation: Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Lienenklaus
authors.affiliation: Sahlgrenska Cancer Center, University of Gothenburg, 41390 Gothenburg, Sweden.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Nilsson
authors.affiliation: Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Kröger
authors.affiliation: Sahlgrenska Cancer Center, University of Gothenburg, 41390 Gothenburg, Sweden.
authors.forename: Jonas A
authors.initials: JA
authors.lastname: Nilsson
authors.affiliation: Department of Paediatrics, Hospital of Halland, 30185 Halmstad, Sweden.
authors.forename: Torben
authors.initials: T
authors.lastname: Ek
authors.affiliation: Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany.
authors.forename: Siegfried
authors.initials: S
authors.lastname: Weiss
authors.affiliation: Laboratory for Molecular Infection Medicine Sweden, Umeå University, 90 187 Umeå, Sweden; Department of Molecular Biology, Umeå University, 90 187 Umeå, Sweden; Umeå Centre for Microbial Research, Umeå University, 90 187 Umeå, Sweden. Electronic address: nelson.gekara@mims.umu.se.
authors.forename: Nelson O
authors.initials: NO
authors.lastname: Gekara
mesh_terms: D000818:Animals; D001260:Ataxia Telangiectasia / Q000276:immunology*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics; D001854:Bone Marrow Cells / Q000276:immunology; D002460:Cell Line; D003600:Cytosol / Q000276:immunology / Q000382:microbiology; D004247:DNA / Q000276:immunology*; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics; D004789:Enzyme Activation / Q000276:immunology; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate; D016898:Interferon-alpha / Q000096:biosynthesis; D016899:Interferon-beta / Q000096:biosynthesis; D007371:Interferon-gamma / Q000096:biosynthesis; D008089:Listeria monocytogenes / Q000276:immunology*; D008088:Listeriosis / Q000276:immunology*; D008264:Macrophages / Q000276:immunology; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099197:STING Protein
chemical_list: D064007:Ataxia Telangiectasia Mutated Proteins; D004247:DNA; D016898:Interferon-alpha; D016899:Interferon-beta; D007371:Interferon-gamma; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D048051:p38 Mitogen-Activated Protein Kinases; C530855:Sting1 protein, mouse; D000099197:STING Protein; C498588:Tbk1 protein, mouse; C576325:Atm protein, mouse