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AIM2/ASC triggers caspase-8-dependent apoptosis in Francisella-infected caspase-1-deficient macrophages

R Pierini1, C Juruj, M Perret

  • 1Université de Lyon, France.

Cell Death and Differentiation
|May 5, 2012
PubMed

Insights

The AIM2/ASC inflammasome complex activates caspase-8, initiating apoptosis independently of caspase-1. This novel AIM2-ASC-dependent pathway restricts bacterial growth and controls immune responses.

Area of Science:

  • Immunology
  • Cell Biology
  • Infectious Disease

Background:

  • The inflammasome, a protein complex, typically activates caspase-1, leading to pyroptosis (a form of cell death).
  • AIM2 (Absent in Melanoma 2) is a sensor for cytosolic DNA, and ASC (Apoptosis-associated speck-like protein containing a CARD) is an adaptor molecule crucial for AIM2-mediated inflammasome activation.
  • The precise functions of the AIM2/ASC complex beyond caspase-1 activation were not fully understood.

Purpose of the Study:

  • To investigate novel functions of the AIM2/ASC complex.
  • To uncover alternative cell death pathways mediated by AIM2/ASC.
  • To understand the role of AIM2/ASC in response to bacterial infection.

Main Methods:

  • Gene inactivation studies comparing different inflammasome pathway components.
  • Analysis of cell death mechanisms (pyroptosis vs. apoptosis) in macrophages infected with Francisella tularensis.
  • Biochemical assays to detect protein interactions and caspase activation (caspase-1, -3, -8, -9).
  • In vitro bacterial replication assays and in vivo IFN-γ level measurements in Caspase-1 knockout mice.

Main Results:

  • A novel AIM2/ASC-dependent cell death pathway was identified, distinct from caspase-1 activation.
  • In caspase-1-deficient macrophages, Francisella tularensis triggered AIM2/ASC-dependent apoptosis mediated by caspase-3.
  • AIM2 engagement led to caspase-1-independent activation of caspase-8 and caspase-9, with caspase-8 interacting with ASC.
  • This pathway functions as an innate immune mechanism restricting bacterial replication in vitro and controlling IFN-γ levels in vivo.

Conclusions:

  • The AIM2/ASC complex acts as a platform for caspase-8 activation, initiating apoptosis independently of caspase-1.
  • This pathway represents a versatile innate immune response, capable of switching from pyroptosis to apoptosis.
  • The findings reveal a significant crosstalk between inflammasome components and the apoptotic machinery.

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