Flightless-I regulates proinflammatory caspases by selectively modulating intracellular localization and caspase activity.
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.
Li
Juying
J
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Yin
Helen L
HL
Yuan
Junying
J
D000199:Actins / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D019921:Biotinylation; D002352:Carrier Proteins; D020170:Caspase 1 / Q000378:metabolism*; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D053471:Caspases, Initiator; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism*; D004789:Enzyme Activation; D053583:Interleukin-1beta / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D008840:Microfilament Proteins; D008969:Molecular Sequence Data; D016366:Open Reading Frames; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D010957:Plasmids; D015534:Trans-Activators
D000199:Actins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; C000609263:FlII protein, mouse; D053583:Interleukin-1beta; D008840:Microfilament Proteins; D010446:Peptide Fragments; D015534:Trans-Activators; C101136:Casp4 protein, mouse; D020169:Caspases; D053471:Caspases, Initiator; D020170:Caspase 1