title: Unified polymerization mechanism for the assembly of ASC-dependent inflammasomes.
abstract: Inflammasomes elicit host defense inside cells by activating caspase-1 for cytokine maturation and cell death. AIM2 and NLRP3 are representative sensor proteins in two major families of inflammasomes. The adaptor protein ASC bridges the sensor proteins and caspase-1 to form ternary inflammasome complexes, achieved through pyrin domain (PYD) interactions between sensors and ASC and through caspase activation and recruitment domain (CARD) interactions between ASC and caspase-1. We found that PYD and CARD both form filaments. Activated AIM2 and NLRP3 nucleate PYD filaments of ASC, which, in turn, cluster the CARD of ASC. ASC thus nucleates CARD filaments of caspase-1, leading to proximity-induced activation. Endogenous NLRP3 inflammasome is also filamentous. The cryoelectron microscopy structure of ASC(PYD) filament at near-atomic resolution provides a template for homo- and hetero-PYD/PYD associations, as confirmed by structure-guided mutagenesis. We propose that ASC-dependent inflammasomes in both families share a unified assembly mechanism that involves two successive steps of nucleation-induced polymerization. PAPERFLICK:
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Alvin
authors.initials: A
authors.lastname: Lu
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Venkat Giri
authors.initials: VG
authors.lastname: Magupalli
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Jianbin
authors.initials: J
authors.lastname: Ruan
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Yin
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Maninjay K
authors.initials: MK
authors.lastname: Atianand
authors.affiliation: FEI Company, Nanoport Europe, 5651 GG Eindhoven, the Netherlands.
authors.forename: Matthijn R
authors.initials: MR
authors.lastname: Vos
authors.affiliation: Institute of Complex Systems, Forschungszentrum Jülich, 52425 Jülich, Germany; Physics Department, Heinrich-Heine Universität Düsseldorf, 40225 Düsseldorf, Germany.
authors.forename: Gunnar F
authors.initials: GF
authors.lastname: Schröder
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA. Electronic address: hao.wu@childrens.harvard.edu.
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Edward H
authors.initials: EH
authors.lastname: Egelman
mesh_terms: D000595:Amino Acid Sequence; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000378:metabolism; D020285:Cryoelectron Microscopy; D003598:Cytoskeletal Proteins / Q000737:chemistry* / Q000378:metabolism*; D004268:DNA-Binding Proteins; D006801:Humans; D058847:Inflammasomes / Q000737:chemistry* / Q000378:metabolism / Q000648:ultrastructure; D053583:Interleukin-1beta / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009687:Nuclear Proteins / Q000378:metabolism; D058105:Polymerization; D017434:Protein Structure, Tertiary
chemical_list: C410167:AIM2 protein, human; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D009687:Nuclear Proteins; C402202:PYCARD protein, human