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ASC filament formation serves as a signal amplification mechanism for inflammasomes

Dick, Mathias S., Sborgi, Lorenzo, Rühl, Sebastian, Hiller, Sebastian, Broz, Petr·2016·Nature Communications
DOI 10.1038/ncomms11929PMC PMC4917984
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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.

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Metadata

Authors
Dick, M. S., Sborgi, L., Rühl, S., Hiller, S., & Broz, P.
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2016-06-22
Volume
7
Issue
1
ISSN
2041-1723
DOI
10.1038/ncomms11929
PMC
PMC4917984
Cited by
394
References
13
Language
en
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correction (2017-03-17)
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