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Cell. 2014 Mar 13;156(6):1193-1206. doi: 10.1016/j.cell.2014.02.008.

Unified polymerization mechanism for the assembly of ASC-dependent inflammasomes.

Author information

1
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.
2
Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA.
3
FEI Company, Nanoport Europe, 5651 GG Eindhoven, the Netherlands.
4
Institute of Complex Systems, Forschungszentrum Jülich, 52425 Jülich, Germany; Physics Department, Heinrich-Heine Universität Düsseldorf, 40225 Düsseldorf, Germany.
5
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.
6
Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA.

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.

PMID:
24630722
PMCID:
PMC4000066
DOI:
10.1016/j.cell.2014.02.008
[Indexed for MEDLINE]
Free PMC Article

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