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Activation and Measurement of NLRP3 Inflammasome Activity Using IL-1β in Human Monocyte-derived Dendritic Cells
Published on: May 22, 2014
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Structural basis for distinct inflammasome complex assembly by human NLRP1 and CARD8
Qin Gong1,2, Kim Robinson3, Chenrui Xu1,2
1School of Biological Sciences, Nanyang Technological University, Singapore, 637551, Singapore.
Nature Communications
|January 9, 2021
Summary
Nod-like receptor (NLR) proteins NLRP1 and CARD8 activate inflammation through unique self-assembly mechanisms. Structural studies reveal how these inflammasome proteins discriminate targets, offering insights into auto-inflammatory diseases.
Area of Science:
- Immunology
- Structural Biology
- Molecular Biology
Background:
- Nod-like receptor (NLR) proteins are key regulators of inflammation and cell death.
- NLRP1 and CARD8 are sensor proteins involved in inflammasome activation and auto-inflammatory diseases.
- Their precise activation mechanisms remain largely unelucidated.
Purpose of the Study:
- To elucidate the structural basis of NLRP1 and CARD8 inflammasome complex assembly and activation.
- To understand how NLRP1 and CARD8 discriminate between ASC and pro-caspase-1.
- To provide insights into the molecular mechanisms underlying auto-inflammatory conditions.
Main Methods:
- Recombinant expression and purification of NLRP1 and CARD8 FIIND-CARD domains.
- Biochemical assays to assess self-oligomerization and ASC speck formation.
- Cryo-electron microscopy (cryo-EM) to determine high-resolution structures of filament assemblies.
Main Results:
- NLRP1 FIIND-CARD self-oligomerizes into a two-layered filament structure.
- NLRP1-CARD filaments drive ASC speck formation, enhanced by NLRP1-FIIND.
- Cryo-EM structures reveal unique features enabling discrimination of ASC and pro-caspase-1.
Conclusions:
- Structural insights into the auto-proteolysis-dependent activation of NLRP1 and CARD8 inflammasomes.
- Demonstration of distinct filament assembly and target discrimination mechanisms for NLRP1 and CARD8.
- Findings illuminate pathways for highly specific signaling in inflammasome complexes and potential therapeutic targets for auto-inflammatory diseases.
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