ASC filament formation serves as a signal amplification mechanism for inflammasomes
| Autor: | Dick Mathias S, Sborgi Lorenzo, Rühl Sebastian, Hiller Sebastian, Broz Petr |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
endocrine system
Inflammasomes Science animal diseases Interleukin-1beta Apoptosis Bone Marrow Cells Mice Protein Domains NLR Family Pyrin Domain-Containing 3 Protein Pyroptosis Animals Humans Macrophages Caspase 1 Intracellular Signaling Peptides and Proteins hemic and immune systems Phosphate-Binding Proteins Corrigenda eye diseases CARD Signaling Adaptor Proteins Enzyme Activation Mice Inbred C57BL Kinetics HEK293 Cells Mutation Mutagenesis Site-Directed CRISPR-Cas Systems Apoptosis Regulatory Proteins tissues Signal Transduction |
| Zdroj: | Nature Communications Nature Communications, Vol 7, Iss 1, Pp 1-13 (2016) Nature communications |
| Popis: | A hallmark of inflammasome activation is the ASC speck, a micrometre-sized structure formed by the inflammasome adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD), which consists of a pyrin domain (PYD) and a caspase recruitment domain (CARD). Here we show that assembly of the ASC speck involves oligomerization of ASC(PYD) into filaments and cross-linking of these filaments by ASC(CARD). ASC mutants with a non-functional CARD only assemble filaments but not specks, and moreover disrupt endogenous specks in primary macrophages. Systematic site-directed mutagenesis of ASC(PYD) is used to identify oligomerization-deficient ASC mutants and demonstrate that ASC speck formation is required for efficient processing of IL-1β, but dispensable for gasdermin-D cleavage and pyroptosis induction. Our results suggest that the oligomerization of ASC creates a multitude of potential caspase-1 activation sites, thus serving as a signal amplification mechanism for inflammasome-mediated cytokine production. |
| Databáze: | OpenAIRE |
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