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Structural mechanisms of inflammasome assembly
1Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Cambridge, MA, USA; Chemical Biology PhD Program, Harvard University, Cambridge, MA, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA.
The FEBS Journal
|October 30, 2014
Summary
Inflammasomes are protein complexes that trigger host defense by activating inflammatory caspases and cytokines. Their assembly involves filamentous structures with prion-like properties, crucial for cellular defense signaling.
Area of Science:
- Immunology
- Molecular Biology
- Cellular Biology
Background:
- Inflammasomes are multiprotein complexes mediating innate immunity.
- They activate inflammatory caspases (e.g., caspase 1) for cytokine maturation (IL-1β, IL-18) and pyroptosis.
- Assembly requires sensors, effectors, and adaptors like ASC (apoptosis-associated speck-like protein containing a CARD).
Purpose of the Study:
- To review current understandings of inflammasome structures.
- To explore the mechanisms governing inflammasome assembly and regulation.
- To discuss the functional implications of inflammasome architecture.
Main Methods:
- Review of traditional structural methods.
- Biochemical and biophysical analyses.
- Single-molecule studies.
Main Results:
- Inflammasome assembly is scaffolded by Pyrin and CARD domain-containing filaments.
- Nucleated polymerization governs ordered assembly from sensor activation to effector caspase activation.
- Filamentous architecture and cooperativity explain "all-or-none" activation and may involve prion-like propagation.
Conclusions:
- Inflammasome structure is characterized by filamentous assemblies of Pyrin and CARD domains.
- Ordered, cooperative polymerization drives inflammasome activation, potentially through prion-like mechanisms.
- Cytosolic inhibitors regulate inflammasome assembly kinetics and morphology.
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