Unified polymerization mechanism for the assembly of ASC-dependent inflammasomes

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 comp...

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Veröffentlicht in:Cell Jg. 156; H. 6; S. 1193
Hauptverfasser: Lu, Alvin, Magupalli, Venkat Giri, Ruan, Jianbin, Yin, Qian, Atianand, Maninjay K, Vos, Matthijn R, Schröder, Gunnar F, Fitzgerald, Katherine A, Wu, Hao, Egelman, Edward H
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 13.03.2014
Schlagworte:
Amino Acid Sequence
CARD Signaling Adaptor Proteins
Carrier Proteins - metabolism
Cryoelectron Microscopy
Cytoskeletal Proteins - chemistry
Cytoskeletal Proteins - metabolism
DNA-Binding Proteins
Humans
Inflammasomes - chemistry
Inflammasomes - metabolism
Inflammasomes - ultrastructure
Interleukin-1beta - metabolism
Models, Molecular
Molecular Sequence Data
NLR Family, Pyrin Domain-Containing 3 Protein
Nuclear Proteins - metabolism
Polymerization
Protein Structure, Tertiary
ISSN:1097-4172, 1097-4172
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Zusammenfassung: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:
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ISSN:1097-4172
1097-4172
DOI:10.1016/j.cell.2014.02.008