Caspase-1 Activity Affects AIM2 Speck formation/stability Through a Negative Feedback Loop

Front Cell Infect Microbiol. 2013 Apr 24;3:14. doi: 10.3389/fcimb.2013.00014. eCollection 2013.

Abstract

The inflammasome is an innate immune signaling platform leading to caspase-1 activation, maturation of pro-inflammatory cytokines and cell death. Recognition of DNA within the host cytosol induces the formation of a large complex composed of the AIM2 receptor, the ASC adaptor and the caspase-1 effector. Francisella tularensis, the agent of tularemia, replicates within the host cytosol. The macrophage cytosolic surveillance system detects Francisella through the AIM2 inflammasome. Upon Francisella novicida infection, we observed a faster kinetics of AIM2 speck formation in ASC(KO) and Casp1(KO) as compared to WT macrophages. This observation was validated by a biochemical approach thus demonstrating for the first time the existence of a negative feedback loop controlled by ASC/caspase-1 that regulates AIM2 complex formation/stability. This regulatory mechanism acted before pyroptosis and required caspase-1 catalytic activity. Our data suggest that sublytic caspase-1 activity could delay the formation of stable AIM2 speck, an inflammasome complex associated with cell death.

Keywords: AIM2; Francisella tularensis; caspase-1; inflammasome; regulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins
  • CARD Signaling Adaptor Proteins
  • Caspase 1 / genetics
  • Caspase 1 / metabolism*
  • Cell Death
  • Cell Line
  • Cytoskeletal Proteins / genetics
  • DNA-Binding Proteins
  • Feedback*
  • Francisella tularensis / immunology*
  • Gene Deletion
  • Humans
  • Macrophages / immunology*
  • Macrophages / microbiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nuclear Proteins / metabolism*

Substances

  • Aim2 protein, mouse
  • Apoptosis Regulatory Proteins
  • CARD Signaling Adaptor Proteins
  • Cytoskeletal Proteins
  • DNA-Binding Proteins
  • Nuclear Proteins
  • Pycard protein, mouse
  • Caspase 1