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ASC filament formation serves as a signal amplification mechanism for inflammasomes

Author

Listed:
  • 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)

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.

Suggested Citation

  • Mathias S. Dick & Lorenzo Sborgi & Sebastian Rühl & Sebastian Hiller & Petr Broz, 2016. "ASC filament formation serves as a signal amplification mechanism for inflammasomes," Nature Communications, Nature, vol. 7(1), pages 1-13, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11929
    DOI: 10.1038/ncomms11929
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