title: Noncanonical autophagy is required for type I interferon secretion in response to DNA-immune complexes.
abstract: Toll-like receptor-9 (TLR9) is largely responsible for discriminating self from pathogenic DNA. However, association of host DNA with autoantibodies activates TLR9, inducing the pathogenic secretion of type I interferons (IFNs) from plasmacytoid dendritic cells (pDCs). Here, we found that in response to DNA-containing immune complexes (DNA-IC), but not to soluble ligands, IFN-α production depended upon the convergence of the phagocytic and autophagic pathways, a process called microtubule-associated protein 1A/1B-light chain 3 (LC3)-associated phagocytosis (LAP). LAP was required for TLR9 trafficking into a specialized interferon signaling compartment by a mechanism that involved autophagy-related proteins, but not the conventional autophagic preinitiation complex, or adaptor protein-3 (AP-3). Our findings unveil a new role for nonconventional autophagy in inflammation and provide one mechanism by which anti-DNA autoantibodies, such as those found in several autoimmune disorders, bypass the controls that normally restrict the apportionment of pathogenic DNA and TLR9 to the interferon signaling compartment.
authors.affiliation: Respiratory, Inflammation and Autoimmunity Research Department, Gaithersburg, MD 20878, USA.
authors.forename: Jill
authors.initials: J
authors.lastname: Henault
authors.affiliation: Department Immunology, St. Jude Children's Research Institute, Memphis, TN 38105, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Martinez
authors.affiliation: Respiratory, Inflammation and Autoimmunity Research Department, Gaithersburg, MD 20878, USA.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Riggs
authors.affiliation: Respiratory, Inflammation and Autoimmunity Research Department, Gaithersburg, MD 20878, USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Tian
authors.affiliation: Respiratory, Inflammation and Autoimmunity Research Department, Gaithersburg, MD 20878, USA.
authors.forename: Payal
authors.initials: P
authors.lastname: Mehta
authors.affiliation: Department of Antibody Discovery and Protein Engineering MedImmune, Gaithersburg, MD 20878, USA.
authors.forename: Lorraine
authors.initials: L
authors.lastname: Clarke
authors.affiliation: Department of Immunology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Miwa
authors.initials: M
authors.lastname: Sasai
authors.affiliation: Institute of Innate Immunity, Biomedical Center, 1G008, University Hospitals, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany.
authors.forename: Eicke
authors.initials: E
authors.lastname: Latz
authors.affiliation: Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany.
authors.forename: Melanie M
authors.initials: MM
authors.lastname: Brinkmann
authors.affiliation: Department of Immunology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Akiko
authors.initials: A
authors.lastname: Iwasaki
authors.affiliation: Respiratory, Inflammation and Autoimmunity Research Department, Gaithersburg, MD 20878, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Coyle
authors.affiliation: Respiratory, Inflammation and Autoimmunity Research Department, Gaithersburg, MD 20878, USA.
authors.forename: Roland
authors.initials: R
authors.lastname: Kolbeck
authors.affiliation: Department Immunology, St. Jude Children's Research Institute, Memphis, TN 38105, USA.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Green
authors.affiliation: Respiratory, Inflammation and Autoimmunity Research Department, Gaithersburg, MD 20878, USA.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Sanjuan
mesh_terms: D000818:Animals; D000936:Antigen-Antibody Complex / Q000276:immunology*; D001343:Autophagy / Q000276:immunology*; D004247:DNA / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007370:Interferon Type I / Q000096:biosynthesis*; D026901:Membrane Transport Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D010587:Phagocytosis / Q000276:immunology; D010588:Phagosomes / Q000378:metabolism; D021381:Protein Transport; D051217:Toll-Like Receptor 9 / Q000276:immunology / Q000378:metabolism
chemical_list: D000936:Antigen-Antibody Complex; D007074:Immunoglobulin G; D007370:Interferon Type I; C480860:Map1lc3b protein, mouse; D026901:Membrane Transport Proteins; D008869:Microtubule-Associated Proteins; D051217:Toll-Like Receptor 9; D004247:DNA