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ASC filament formation serves as a signal amplification mechanism for inflammasomes

Dick, Mathias S. and Sborgi, Lorenzo and Rühl, Sebastian and Hiller, Sebastian and Broz, Petr. (2016) ASC filament formation serves as a signal amplification mechanism for inflammasomes. Nature Communications, 7. p. 11929.

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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.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Former Organization Units Biozentrum > Infection Biology (Broz)
05 Faculty of Science > Departement Biozentrum > Structural Biology & Biophysics > Structural Biology (Hiller)
UniBasel Contributors:Broz, Petr and Dick, Mathias S. and Sborgi, Lorenzo and Rühl, Sebastian and Hiller Odermatt, Sebastian
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Springer Nature
e-ISSN:2041-1723
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
Identification Number:
Last Modified:19 Dec 2017 13:24
Deposited On:27 Oct 2016 10:31

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