title: Structures of the HIN domain:DNA complexes reveal ligand binding and activation mechanisms of the AIM2 inflammasome and IFI16 receptor.
abstract: Recognition of DNA by the innate immune system is central to antiviral and antibacterial defenses, as well as an important contributor to autoimmune diseases involving self DNA. AIM2 (absent in melanoma 2) and IFI16 (interferon-inducible protein 16) have been identified as DNA receptors that induce inflammasome formation and interferon production, respectively. Here we present the crystal structures of their HIN domains in complex with double-stranded (ds) DNA. Non-sequence-specific DNA recognition is accomplished through electrostatic attraction between the positively charged HIN domain residues and the dsDNA sugar-phosphate backbone. An intramolecular complex of the AIM2 Pyrin and HIN domains in an autoinhibited state is liberated by DNA binding, which may facilitate the assembly of inflammasomes along the DNA staircase. These findings provide mechanistic insights into dsDNA as the activation trigger and oligomerization platform for the assembly of large innate signaling complexes such as the inflammasomes.
authors.affiliation: Structural Immunobiology Unit, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-0430, USA.
authors.forename: Tengchuan
authors.initials: T
authors.lastname: Jin
authors.forename: Andrew
authors.initials: A
authors.lastname: Perry
authors.forename: Jiansheng
authors.initials: J
authors.lastname: Jiang
authors.forename: Patrick
authors.initials: P
authors.lastname: Smith
authors.forename: James A
authors.initials: JA
authors.lastname: Curry
authors.forename: Leonie
authors.initials: L
authors.lastname: Unterholzner
authors.forename: Zhaozhao
authors.initials: Z
authors.lastname: Jiang
authors.forename: Gabor
authors.initials: G
authors.lastname: Horvath
authors.forename: Vijay A
authors.initials: VA
authors.lastname: Rathinam
authors.forename: Ricky W
authors.initials: RW
authors.lastname: Johnstone
authors.forename: Veit
authors.initials: V
authors.lastname: Hornung
authors.forename: Eicke
authors.initials: E
authors.lastname: Latz
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Bowie
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
authors.forename: T Sam
authors.initials: TS
authors.lastname: Xiao
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D018360:Crystallography, X-Ray; D059371:DNA, B-Form / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry*; D006801:Humans; D007113:Immunity, Innate; D058847:Inflammasomes / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D011485:Protein Binding; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D015398:Signal Transduction
chemical_list: C410167:AIM2 protein, human; D059371:DNA, B-Form; D004268:DNA-Binding Proteins; C101635:HIN-200 protein, human; D058847:Inflammasomes; D009687:Nuclear Proteins; D010750:Phosphoproteins; C076700:IFI16 protein, human