The ASC inflammasome adapter governs the extent of peripheral SAA-derived protein aggregate deposition in inflammation-induced amyloidosis
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB76882 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR13316876.fastq.gz | Fastqsanger.gz | |||
| ERR13316877.fastq.gz | Fastqsanger.gz | |||
| ERR13316878.fastq.gz | Fastqsanger.gz | |||
| ERR13316879.fastq.gz | Fastqsanger.gz | |||
| ERR13316880.fastq.gz | Fastqsanger.gz |
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Project description:Extracellularly released molecular inflammasome assemblies -ASC specks- cross-seed Aβ amyloid in Alzheimer's disease. Here we show that ASC governs the extent of inflammation-induced amyloid A (AA) amyloidosis, a systemic disease caused by the aggregation and peripheral deposition of the acute-phase reactant serum amyloid A (SAA) in chronic inflammatory conditions. Using super-resolution microscopy, we found that ASC colocalized tightly with SAA in human AA amyloidosis. Recombinant ASC specks accelerated SAA fibril formation and mass spectrometry after limited proteolysis showed that ASC interacts with SAA via its pyrin domain (PYD). In a murine model of inflammatory AA amyloidosis, splenic amyloid load was conspicuously decreased in Pycard-/- mice which lack ASC. Treatment with anti-ASCPYD antibodies decreased amyloid loads in wild-type mice suffering from AA amyloidosis. The prevalence of natural anti-ASC IgG (-logEC50 ≥ 2) in 19,334 hospital patients was <0.01%, suggesting that anti-ASC antibody treatment modalities would not be confounded by natural autoimmunity. These findings expand the role played by ASC and IL-1 independent inflammasome employments to extraneural proteinopathies and suggest that anti-ASC immunotherapy may contribute to resolving such diseases.
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Project description:Extracellularly released molecular inflammasome assemblies (ASC specks) cross-seed Aβ amyloid in Alzheimer's disease. Here we show that ASC governs the extent of inflammation-induced amyloid A (AA) amyloidosis, a systemic disease caused by the aggregation and peripheral deposition of the acute-phase reactant serum amyloid A (SAA) in chronic inflammatory conditions. Using superresolution microscopy, we found that ASC colocalized tightly with SAA in human AA amyloidosis. Recombinant ASC specks accelerated SAA fibril formation and mass spectrometry after limited proteolysis showed that ASC interacts with SAA via its pyrin domain (PYD). In a murine model of inflammatory AA amyloidosis, splenic amyloid load was conspicuously decreased in Pycard-/- mice which lack ASC. Treatment with anti-ASC(PYD) antibodies decreased amyloid loads in wildtype mice suffering from AA amyloidosis. The prevalence of natural anti-ASC IgG (-logEC50{greater than or equal to}2) in 19,334 hospital patients was <0.01%, suggesting that anti-ASC antibody treatment modalities would not be confounded by natural autoimmunity. These findings expand the role played by ASC and IL-1 independent inflammasome employments to extraneural proteinopathies and suggest that anti-ASC immunotherapy may contribute to resolving such diseases.
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Project description:ASC (apoptosis-associated speck-like protein containing a CARD) is a modular protein that functions as an adapter of the inflammasome, a multi-protein complex that triggers the inflammatory response in the presence of infection or cell damage. ASC bridges the inflammasome components (PYD-containing sensors and procaspase 1) via homotypic interactions mediated by its two death domains, PYD and CARD. The self-assembly and oligomerization of multiple copies of these three proteins result in the activation of procaspase 1, in turn rendering different cytokines functional. An in-depth understanding of ASC binding capabilities is crucial to decipher the molecular mechanisms of its role in inflammasome formation. In this chapter, we discuss the use of solution NMR to identify specific interacting surfaces of the inflammasome adapter ASC, and describe detailed protocols to perform NMR titrations with Death Domains to obtain apparent dissociation constants of the resulting complexes. The incorporation of NMR restraints in molecular docking to obtain models of these protein assemblies is presented.
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Project description:Upon activation of ASC-containing inflammasomes, intracellular molecular aggregates (ASC specks) are assembled and released from myeloid cells into the extracellular space where they enhance the aggregation of Aβ amyloid in Alzheimer’s disease. This raises the question whether ASC is involved in additional aggregation proteinopathies. In this study we report that ASC governs the extent of inflammation-induced amyloid A (AA) amyloidosis, a systemic disease caused by the aggregation and peripheral deposition of the acute-phase reactant serum amyloid A (SAA).
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Project description:The inflammasome is a multiprotein complex necessary for the onset of inflammation. The adapter protein ASC assembles inflammasome components by acting as a molecular glue between danger-signal sensors and procaspase-1. The assembly is mediated by ASC self-association and protein interactions via its two Death Domains, PYD and CARD. Truncated versions of ASC have been shown to form filaments, but information on the filaments formed by full-length ASC is needed to construct a meaningful model of inflammasome assembly. To gain insights into this system, we used a combination of transmission EM, NMR, and computational analysis to investigate intact ASC structures. We show that ASC forms ∼6-7-nm-wide filaments that stack laterally to form bundles. The structural characteristics and dimensions of the bundles indicate that both PYD and CARD are integral parts of the filament. A truncated version of ASC with only the CARD domain (ASCCARD) forms different filaments (∼3-4-nm width), providing further evidence that both domains work in concert in filament assembly. Ring-shaped protein particles bound to pre-existing filaments match the size of ASC dimer structures generated by NMR-based protein docking, suggesting that the ASC dimer could be a basic building block for filament formation. Solution NMR binding studies identified the protein surfaces involved in the ASCCARD-ASCCARD interaction. These data provide new insights into the structural underpinnings of the inflammasome and should inform future efforts to interrogate this important biological system.
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