ASC filament formation serves as a signal amplification mechanism for inflammasomes

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Apoptosis Regulatory Proteins / chemistry
  • Bone Marrow Cells / cytology*
  • CARD Signaling Adaptor Proteins / chemistry*
  • CRISPR-Cas Systems
  • Caspase 1 / chemistry
  • Enzyme Activation
  • HEK293 Cells
  • Humans
  • Inflammasomes / metabolism*
  • Interleukin-1beta / metabolism
  • Intracellular Signaling Peptides and Proteins
  • Kinetics
  • Macrophages / cytology*
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mutagenesis, Site-Directed
  • Mutation
  • NLR Family, Pyrin Domain-Containing 3 Protein / chemistry
  • Phosphate-Binding Proteins
  • Protein Domains
  • Pyroptosis
  • Signal Transduction


  • Apoptosis Regulatory Proteins
  • CARD Signaling Adaptor Proteins
  • Gsdmd protein, mouse
  • Inflammasomes
  • Interleukin-1beta
  • Intracellular Signaling Peptides and Proteins
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Phosphate-Binding Proteins
  • Pycard protein, mouse
  • Caspase 1