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AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA

Teresa Fernandes-Alnemri1, Je-Wook Yu, Pinaki Datta

  • 1Department of Biochemistry and Molecular Biology, Center for Apoptosis Research, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.

Nature
|January 23, 2009
PubMed

Insights

The absent in melanoma 2 (AIM2) inflammasome senses cytoplasmic DNA, activating caspase-1 and pyroptosis. This discovery reveals AIM2

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Biology

Background:

  • Cytoplasmic double-stranded DNA from hosts or pathogens activates inflammasomes.
  • Inflammasome activation leads to caspase-1 activation and pro-interleukin-1beta maturation.
  • The specific sensor for cytoplasmic DNA in inflammasome activation remained unidentified.

Purpose of the Study:

  • To identify the sensor protein responsible for cytoplasmic DNA-triggered inflammasome activation.
  • To elucidate the mechanism by which cytoplasmic DNA activates the inflammasome.
  • To characterize the role of AIM2 in inflammasome and pyroptosome formation.

Main Methods:

  • Utilized short interfering RNA (siRNA) to knockdown AIM2 expression in macrophages.
  • Assessed inflammasome and pyroptosome activation in response to cytoplasmic DNA.
  • Expressed AIM2 in a non-responsive cell line (HEK293T) to test for induced responsiveness.

Main Results:

  • Absent in melanoma 2 (AIM2) was identified as the cytoplasmic DNA sensor.
  • AIM2's oligonucleotide/oligosaccharide-binding (OB) domain senses DNA, while its pyrin domain interacts with ASC.
  • AIM2 activation leads to ASC pyroptosome formation, caspase-1 activation, and pyroptotic cell death.

Conclusions:

  • AIM2 is a crucial component of the inflammasome that detects cytoplasmic DNA.
  • AIM2 oligomerization is induced by cytoplasmic DNA, initiating inflammasome assembly.
  • The AIM2-ASC interaction triggers caspase-1 activation and pyroptosis, crucial innate immune responses.

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