4.8 Article

ASC filament formation serves as a signal amplification mechanism for inflammasomes

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NATURE COMMUNICATIONS
卷 7, 期 -, 页码 -

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NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms11929

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  1. Swiss National Science Foundation [PP00P3_139120/1]
  2. Swiss National Science Foundation (SNF) [PP00P3_139120] Funding Source: Swiss National Science Foundation (SNF)

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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-1 beta, 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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