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Nat Commun. 2016 Jun 22;7:11929. doi: 10.1038/ncomms11929.

ASC filament formation serves as a signal amplification mechanism for inflammasomes.

Author information

1
Focal Area Infection Biology, Biozentrum, University of Basel, Klingelbergstrasse 50/70, 4056 Basel, Switzerland.
2
Focal Area Structural Biology, Biozentrum, University of Basel, Klingelbergstrasse 50/70, 4056 Basel, Switzerland.

Abstract

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.

PMID:
27329339
PMCID:
PMC4917984
DOI:
10.1038/ncomms11929
[Indexed for MEDLINE]
Free PMC Article

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