Cryopyrin and pyrin activate caspase-1, but not NF-kappaB, via ASC oligomerization.
Mutations in cryopyrin and pyrin proteins are responsible for several autoinflammatory disorders in humans, suggesting that these proteins play important roles in regulating inflammation. Using a HEK293 cell-based reconstitution system that stably expresses ASC and procaspase-1 we demonstrated that neither cryopyrin nor pyrin or their corresponding disease-associated mutants could significantly activate NF-kappaB in this system. However, both cryopyrin and two disease-associated cryopyrin mutants induced ASC oligomerization and ASC-dependent caspase-1 activation, with the disease-associated mutants being more potent than the wild-type (WT) cryopyrin, because of increased self-oligomerization. Contrary to the proposed anti-inflammatory activity of WT pyrin, our results demonstrated that pyrin, like cryopyrin, can also assemble an inflammasome complex with ASC and procaspase-1 leading to ASC oligomerization, caspase-1 activation and interleukin-1beta processing. Thus, we propose that pyrin could function as a proinflammatory molecule.
Yu
J-W
JW
Department of Microbiology and Immunology, Center for Apoptosis Research, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Wu
J
J
Zhang
Z
Z
Datta
P
P
Ibrahimi
I
I
Taniguchi
S
S
Sagara
J
J
Fernandes-Alnemri
T
T
Alnemri
E S
ES
D016367:Baculoviridae; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006801:Humans; D047468:Immunoprecipitation; D007249:Inflammation / Q000235:genetics / Q000503:physiopathology; D018613:Microscopy, Confocal; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics / Q000502:physiology*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D017434:Protein Structure, Tertiary; D000071198:Pyrin
D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; C000604192:MEFV protein, human; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C402202:PYCARD protein, human; D000071198:Pyrin; D020170:Caspase 1