Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3.
Missense mutations in the CIAS1 gene cause three autoinflammatory disorders: familial cold autoinflammatory syndrome, Muckle-Wells syndrome and neonatal-onset multiple-system inflammatory disease. Cryopyrin (also called Nalp3), the product of CIAS1, is a member of the NOD-LRR protein family that has been linked to the activation of intracellular host defence signalling pathways. Cryopyrin forms a multi-protein complex termed 'the inflammasome', which contains the apoptosis-associated speck-like protein (ASC) and caspase-1, and promotes caspase-1 activation and processing of pro-interleukin (IL)-1beta (ref. 4). Here we show the effect of cryopyrin deficiency on inflammasome function and immune responses. Cryopyrin and ASC are essential for caspase-1 activation and IL-1beta and IL-18 production in response to bacterial RNA and the imidazoquinoline compounds R837 and R848. In contrast, secretion of tumour-necrosis factor-alpha and IL-6, as well as activation of NF-kappaB and mitogen-activated protein kinases (MAPKs) were unaffected by cryopyrin deficiency. Furthermore, we show that Toll-like receptors and cryopyrin control the secretion of IL-1beta and IL-18 through different intracellular pathways. These results reveal a critical role for cryopyrin in host defence through bacterial RNA-mediated activation of caspase-1, and provide insights regarding the pathogenesis of autoinflammatory syndromes.
Kanneganti
Thirumala-Devi
TD
University of Michigan Medical School, Department of Pathology and Comprehensive Cancer Center, Ann Arbor, Michigan 48109, USA.
Ozören
Nesrin
N
Body-Malapel
Mathilde
M
Amer
Amal
A
Park
Jong-Hwan
JH
Franchi
Luigi
L
Whitfield
Joel
J
Barchet
Winfried
W
Colonna
Marco
M
Vandenabeele
Peter
P
Bertin
John
J
Coyle
Anthony
A
Grant
Ethan P
EP
Akira
Shizuo
S
Núñez
Gabriel
G
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism*; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D007093:Imidazoles / Q000494:pharmacology; D000077271:Imiquimod; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism; D007375:Interleukin-1 / Q000276:immunology / Q000378:metabolism; D020382:Interleukin-18 / Q000276:immunology / Q000378:metabolism; D016952:Legionella pneumophila / Q000235:genetics / Q000276:immunology; D008089:Listeria monocytogenes / Q000235:genetics / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D012329:RNA, Bacterial / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D051193:Toll-Like Receptors / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000276:immunology
D048868:Adaptor Proteins, Signal Transducing; D000634:Aminoquinolines; D000998:Antiviral Agents; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D007093:Imidazoles; D007375:Interleukin-1; D020382:Interleukin-18; D046912:Multiprotein Complexes; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C498534:Pycard protein, mouse; D012329:RNA, Bacterial; D051193:Toll-Like Receptors; D020928:Mitogen-Activated Protein Kinases; D020170:Caspase 1; D000077271:Imiquimod; C402365:resiquimod