CARDINAL, a novel caspase recruitment domain protein, is an inhibitor of multiple NF-kappa B activation pathways.
Proteins possessing the caspase recruitment domain (CARD) motif have been implicated in pathways leading to activation of caspases or NF-kappaB in the context of apoptosis or inflammation, respectively. Here we report the identification of a novel protein, CARDINAL, that contains a CARD motif and also exhibits a high degree of homology to the C terminus of DEFCAP/NAC, a recently described member of the Apaf-1/Nod-1 family. In contrast with the majority of CARD proteins described to date, CARDINAL failed to promote apoptosis or NF-kappaB activation. Rather, CARDINAL potently suppressed NF-kappaB activation associated with overexpression of TRAIL-R1, TRAIL-R2, RIP, RICK, Bcl10, and TRADD, or through ligand-induced stimulation of the interleukin-1 or tumor necrosis factor receptors. Co-immunoprecipitation experiments revealed that CARDINAL interacts with the regulatory subunit of the IkappaB kinase (IKK) complex, IKKgamma (NEMO), providing a molecular basis for CARDINAL function. Thus, CARDINAL is a novel regulator of NF-kappaB activation in the context of pro-inflammatory signals.
Bouchier-Hayes
L
L
Molecular Cell Biology Laboratory, Department of Genetics, Smurfit Institute, Trinity College, Dublin 2, Ireland.
Conroy
H
H
Egan
H
H
Adrain
C
C
Creagh
E M
EM
MacFarlane
M
M
Martin
S J
SJ
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000737:chemistry / Q000378:metabolism*; D009363:Neoplasm Proteins; D011233:Precipitin Tests; D017386:Sequence Homology, Amino Acid; D013347:Subcellular Fractions / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D053468:CARD Signaling Adaptor Proteins; C455623:CARD8 protein, human; D002352:Carrier Proteins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D020169:Caspases