Nature Immunology 7, 569 - 575 (2006)
Published online: 30 April 2006; | doi:10.1038/ni1344
Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1 via IpafEdward A Miao1, 2, Celia M Alpuche-Aranda4, Monica Dors1, April E Clark1, Martin W Bader2, Samuel I Miller2, 3
& Alan Aderem11
Institute for Systems Biology, Seattle, Washington 98103, USA. 2
Department of Microbiology, University of Washington, Seattle, Washington 98195, USA. 3
Departments of Genome Sciences and Medicine, University of Washington, Seattle, Washington 98195, USA. 4
Experimental Medicine, Medical School, Universidad Nacional Autonoma de Mexico-Hospital Infantil de Mexico Federico Gomez, 06726 Mexico DF, Mexico.
Correspondence should be addressed to Alan Aderem aderem@systemsbiology.org Macrophages respond to Salmonella typhimurium infection via Ipaf, a NACHT–leucine-rich repeat family member that activates caspase-1 and secretion of interleukin 1 . However, the specific microbial salmonella-derived agonist responsible for activating Ipaf is unknown. We show here that cytosolic bacterial flagellin activated caspase-1 through Ipaf but was independent of Toll-like receptor 5, a known flagellin sensor. Stimulation of the Ipaf pathway in macrophages after infection required a functional salmonella pathogenicity island 1 type III secretion system but not the flagellar type III secretion system; furthermore, Ipaf activation could be recapitulated by the introduction of purified flagellin directly into the cytoplasm. These observations raise the possibility that the salmonella pathogenicity island 1 type III secretion system cannot completely exclude 'promiscuous' secretion of flagellin and that the host capitalizes on this 'error' by activating a potent host-defense pathway.
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