Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1beta via Ipaf

Edward A Miao; Celia M Alpuche-Aranda; Monica Dors; April E Clark; Martin W Bader; Samuel I Miller; Alan Aderem

doi:10.1038/ni1344

Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1beta via Ipaf

Nat Immunol. 2006 Jun;7(6):569-75. doi: 10.1038/ni1344. Epub 2006 Apr 30.

Authors

Edward A Miao¹, Celia M Alpuche-Aranda, Monica Dors, April E Clark, Martin W Bader, Samuel I Miller, Alan Aderem

Affiliation

¹ Institute for Systems Biology, Seattle, Washington 98103, USA.

PMID: 16648853
DOI: 10.1038/ni1344

Abstract

Macrophages respond to Salmonella typhimurium infection via Ipaf, a NACHT-leucine-rich repeat family member that activates caspase-1 and secretion of interleukin 1beta. 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.

MeSH terms

Animals
Apoptosis Regulatory Proteins / genetics
Apoptosis Regulatory Proteins / physiology*
Bacterial Proteins / genetics
Bacterial Proteins / immunology
Calcium-Binding Proteins / genetics
Calcium-Binding Proteins / physiology*
Caspase 1 / metabolism*
Cytoplasm / metabolism
Cytoplasm / microbiology
Enzyme Activation
Flagellin / genetics
Flagellin / immunology*
Interleukin-1 / metabolism*
Macrophages / enzymology
Macrophages / immunology
Macrophages / microbiology
Mice
Mice, Mutant Strains
Mutation
Protein Transport
Salmonella Infections / enzymology
Salmonella Infections / genetics
Salmonella Infections / immunology*
Salmonella typhimurium / genetics
Salmonella typhimurium / immunology
Salmonella typhimurium / pathogenicity*
Toll-Like Receptor 5 / genetics
Toll-Like Receptor 5 / physiology

Substances

Apoptosis Regulatory Proteins
Bacterial Proteins
Calcium-Binding Proteins
FljB protein, Salmonella
Interleukin-1
Ipaf protein, mouse
Toll-Like Receptor 5
Flagellin
Caspase 1