Journal
IMMUNITY
Volume 26, Issue 4, Pages 433-443Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2007.03.008
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Funding
- NHLBI NIH HHS [5/T32/HL007517] Funding Source: Medline
- NIAID NIH HHS [AI063331, AI064748] Funding Source: Medline
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Cryopyrin is essential for caspase-1 activation triggered by Toll-like receptor (TLR) ligands in the presence of adenosine triphosphate (ATP). However, the events linking bacterial products and ATP to cryopyrin remain unclear. Here we demonstrate that cryopyrin-mediated caspase-1 activation proceeds independently of TLR signaling, thus dissociating caspase-1 activation and IL-1 beta secretion. Instead, caspase-1 activation required pannexin-1, a hemichannel protein that interacts with the P2X(7) receptor. Direct cytosolic delivery of multiple bacterial products including lipopolysaccharide, but not flagellin, induced caspase-1 activation via cryopyrin in the absence of pannexin-1 activity or ATP stimulation. However, unlike lpaf-dependent caspase-1 activation, stimulation of the pannexin-1-cryopyrin pathway by several intracellular bacteria was independent of a functional bacterial type III secretion system. These results provide evidence for cytosolic delivery and sensing of bacterial molecules as a unifying model for caspase-1 activation and position pannexin-1 as a mechanistic link between bacterial stimuli and the cryopyrin inflammasome.
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