Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text PDF (Full Text) PPT slides of all figures Supplemental Material Index Alert me when this article is cited Citation Map Services Email this article Similar articles in this journal Similar articles in PubMed Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Google Scholar Articles by Li, J. Articles by Yuan, J. PubMed PubMed Citation Articles by Li, J. Articles by Yuan, J. Social Bookmarking                      What's this?

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.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents