ASC is an activating adaptor for NF-kappa B and caspase-8-dependent apoptosis.
ASC is a pro-apoptotic protein containing a pyrin domain (PD) and a caspase-recruitment domain (CARD). A previous study suggests that ASC interacts with Ipaf, a member of the Apaf-1/Nod1 protein family. However, the functional relevance of the interaction has not been determined. Here, we report that co-expression of ASC with Ipaf or oligomerization of ASC induces both apoptosis and NF-kappa B activation. Apoptosis induced through ASC was inhibited by a mutant form of Caspase-8 but not by that of Caspase-1. The PD of ASC physically interacted with Caspase-8 as well as with pyrin, the familial Mediterranean fever gene product. Caspase-8 deficiency rescued mouse fibroblasts from apoptosis induced by ASC oligomerization. Pyrin disrupted the interaction between ASC and Caspase-8, and inhibited both apoptosis and NF-kappa B activation induced by ASC. These findings suggest that ASC is a mediator of NF-kappa B activation and Caspase-8-dependent apoptosis in an Ipaf signaling pathway.
Masumoto
Junya
J
Department of Pathology and Comprehensive Cancer Center, The University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Dowds
Theresa A
TA
Schaner
Philip
P
Chen
Felicia F
FF
Ogura
Yasunori
Y
Li
Mu
M
Zhu
Li
L
Katsuyama
Tsutomu
T
Sagara
Junji
J
Taniguchi
Shun'ichiro
S
Gumucio
Deborah L
DL
Núñez
Gabriel
G
Inohara
Naohiro
N
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D016923:Cell Death; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000378:metabolism* / Q000502:physiology*; D004789:Enzyme Activation; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism; D000071198:Pyrin; D015398:Signal Transduction; D014162:Transfection
D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D003598:Cytoskeletal Proteins; C000604192:MEFV protein, human; C000604193:Mefv protein, mouse; D016328:NF-kappa B; C402202:PYCARD protein, human; D011506:Proteins; C498534:Pycard protein, mouse; D000071198:Pyrin; C505530:CASP8 protein, human; C506433:CASP9 protein, human; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases