Flightless-I regulates proinflammatory caspases by selectively modulating intracellular localization and caspase activity

Authors:
Li J, Yin HL, Yuan J
In:
Source: J Cell Biol
Publication Date: (2008)
Issue: 181(2): 321-33
Research Area:
Cancer Research/Cell Biology
Cells used in publication:
J-774
Species: mouse
Tissue Origin: ascites
Platform:
Nucleofectorâ„¢ I/II/2b
Abstract
Caspase-1 and caspase-11 are proinflammatory caspases that regulate cytokine production and leukocyte migration during pathogen infection. In an attempt to identify new intracellular regulators of caspase-11, we found that Flightless-I, a member of the gelsolin superfamily of actin-remodeling proteins, interacts and regulates both caspase-11 and caspase-1. Flightless-I targets caspase-11 to the Triton X-100-insoluble cytoskeleton fraction and the cell leading edge. In addition, Flightless-I inhibits caspase-1 activation and caspase-1-mediated interleukine-1beta (IL-1beta) maturation. The physiological relevance of these findings is supported by the opposing effects of Flightless-I overexpression and knockdown on caspase-1 activity and IL-1beta maturation. Our results suggest that Flightless-I may be a bona fide caspase-1 inhibitor that acts through a mechanism similar to that of cytokine response modifier A, a potent caspase-1 inhibitor from the cowpox virus. Our study provides a new mechanism controlling the localization and activation of proinflammatory caspases.