title: Assembly-driven activation of the AIM2 foreign-dsDNA sensor provides a polymerization template for downstream ASC.
abstract: AIM2 recognizes foreign dsDNA and assembles into the inflammasome, a filamentous supramolecular signalling platform required to launch innate immune responses. We show here that the pyrin domain of AIM2 (AIM2(PYD)) drives both filament formation and dsDNA binding. In addition, the dsDNA-binding domain of AIM2 also oligomerizes and assists in filament formation. The ability to oligomerize is critical for binding dsDNA, and in turn permits the size of dsDNA to regulate the assembly of the AIM2 polymers. The AIM2(PYD) oligomers define the filamentous structure, and the helical symmetry of the AIM2(PYD) filament is consistent with the filament assembled by the PYD of the downstream adaptor ASC. Our results suggest that the role of AIM2(PYD) is not autoinhibitory, but generating a structural template by coupling ligand binding and oligomerization is a key signal transduction mechanism in the AIM2 inflammasome.
authors.affiliation: Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine Baltimore, Maryland 21205, USA.
authors.forename: Seamus R
authors.initials: SR
authors.lastname: Morrone
authors.affiliation: Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine Baltimore, Maryland 21205, USA.
authors.forename: Mariusz
authors.initials: M
authors.lastname: Matyszewski
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine Charlottesville, Virginia 22908, USA.
authors.forename: Xiong
authors.initials: X
authors.lastname: Yu
authors.affiliation: Microscope Core Facilities, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Delannoy
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine Charlottesville, Virginia 22908, USA.
authors.forename: Edward H
authors.initials: EH
authors.lastname: Egelman
authors.affiliation: Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine Baltimore, Maryland 21205, USA.
authors.forename: Jungsan
authors.initials: J
authors.lastname: Sohn
mesh_terms: D000595:Amino Acid Sequence; D053468:CARD Signaling Adaptor Proteins; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004926:Escherichia coli; D007113:Immunity, Innate; D058847:Inflammasomes; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D058619:Maltose-Binding Proteins / Q000378:metabolism; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D016296:Mutagenesis
chemical_list: C410167:AIM2 protein, human; D053468:CARD Signaling Adaptor Proteins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; C092537:Ifi202b protein, mouse; D058847:Inflammasomes; D047908:Intracellular Signaling Peptides and Proteins; D058619:Maltose-Binding Proteins; C402202:PYCARD protein, human; D004247:DNA