Pannexin-1-mediated recognition of bacterial molecules activates the cryopyrin inflammasome independent of Toll-like receptor signaling.
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-1beta 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 Ipaf-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.
Kanneganti
Thirumala-Devi
TD
Department of Pathology, Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
Lamkanfi
Mohamed
M
Kim
Yun-Gi
YG
Chen
Grace
G
Park
Jong-Hwan
JH
Franchi
Luigi
L
Vandenabeele
Peter
P
Núñez
Gabriel
G
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001419:Bacteria / Q000276:immunology*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism; D017630:Connexins; D003600:Cytosol / Q000276:immunology / Q000382:microbiology; D004789:Enzyme Activation; D007249:Inflammation / Q000276:immunology; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology* / Q000494:pharmacology; D051379:Mice; D008817:Mice, Mutant Strains; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058486:Receptors, Purinergic P2X7; D051193:Toll-Like Receptors / Q000276:immunology
D051017:Apoptosis Regulatory Proteins; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D017630:Connexins; D053583:Interleukin-1beta; C512299:Ipaf protein, mouse; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009419:Nerve Tissue Proteins; C492716:Nlrp3 protein, mouse; C546469:P2rx7 protein, mouse; C503631:Panx1 protein, mouse; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D051193:Toll-Like Receptors; D020170:Caspase 1