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Published online April 14, 2008
doi:10.1083/jcb.200711082
The Journal of Cell Biology, Vol. 181, No. 2, 321-333
The Rockefeller University Press, 0021-9525 $30.00
© 2008 Li et al.
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Article

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



Juying Li1, Helen L. Yin2, and Junying Yuan1

1 Department of Cell Biology, Harvard Medical School, Boston, MA 02115
2 Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390

Correspondence to J. Yuan: jyuan{at}hms.harvard.edu

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-1β (IL-1β) 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-1β 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.

Abbreviations used in this paper: Aip1, actin-interacting protein 1; CARD, caspase recruitment domain; CrmA, cytokine response modifier A; GLD, gelsolin-like domain; HSS, high-speed supernatant; IL-1β, interleukine-1β; LPS, lipopolysaccharide; LRR, leucine-rich repeat; LRRFIP2, LRR in Flightless-I–interacting protein 2; LSP, low-speed pellet; shRNA, short hairpin RNA; TLR, toll-like receptor; wt, wild type.


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