ASC filament formation serves as a signal amplification mechanism for inflammasomes

Mathias S. Dick, Lorenzo Sborgi, Sebastian Rühl, Sebastian Hiller and Petr Broz ()
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Mathias S. Dick: Focal Area Infection Biology, Biozentrum, University of Basel
Lorenzo Sborgi: Focal Area Structural Biology, Biozentrum, University of Basel
Sebastian Rühl: Focal Area Infection Biology, Biozentrum, University of Basel
Sebastian Hiller: Focal Area Structural Biology, Biozentrum, University of Basel
Petr Broz: Focal Area Infection Biology, Biozentrum, University of Basel

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: 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 ASCPYD into filaments and cross-linking of these filaments by ASCCARD. 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 ASCPYD 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.

Date: 2016
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11929

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DOI: 10.1038/ncomms11929

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