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PMID:10364242
| Citation |
Srinivasula, SM, Ahmad, M, Lin, JH, Poyet, JL, Fernandes-Alnemri, T, Tsichlis, PN and Alnemri, ES (1999) CLAP, a novel caspase recruitment domain-containing protein in the tumor necrosis factor receptor pathway, regulates NF-kappaB activation and apoptosis. J. Biol. Chem. 274:17946-54 |
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| Abstract |
Molecules that regulate NF-kappaB activation play critical roles in apoptosis and inflammation. We describe the cloning of the cellular homolog of the equine herpesvirus-2 protein E10 and show that both proteins regulate apoptosis and NF-kappaB activation. These proteins were found to contain N-terminal caspase-recruitment domains (CARDs) and novel C-terminal domains (CTDs) and were therefore named CLAPs (CARD-like apoptotic proteins). The cellular and viral CLAPs induce apoptosis downstream of caspase-8 by activating the Apaf-1-caspase-9 pathway and activate NF-kappaB by acting upstream of the NF-kappaB-inducing kinase, NIK, and the IkB kinase, IKKalpha. Deletion of either the CARD or the CTD domain inhibits both activities. The CARD domain was found to be important for homo- and heterodimerization of CLAPs. Substitution of the CARD domain with an inducible FKBP12 oligomerization domain produced a molecule that can induce NF-kappaB activation, suggesting that the CARD domain functions as an oligomerization domain, whereas the CTD domain functions as the effector domain in the NF-kappaB activation pathway. Expression of the CARD domain of human CLAP abrogates tumor necrosis factor-alpha-induced NF-kappaB activation, suggesting that cellular CLAP plays an essential role in this pathway of NF-kappaB activation. |
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| Keywords |
Adaptor Proteins, Signal Transducing; Amino Acid Sequence; Apoptosis; Carrier Proteins/chemistry; Carrier Proteins/genetics; Cell Line; Cloning, Molecular; Genes, Reporter; Humans; I-kappa B Kinase; Molecular Sequence Data; NF-kappa B/metabolism; Protein-Serine-Threonine Kinases/genetics; Proteins/chemistry; Proteins/genetics; RNA, Messenger/metabolism; Receptors, Tumor Necrosis Factor/metabolism; Sequence Alignment; Signal Transduction; Transfection; Tumor Necrosis Factor-alpha/pharmacology; Viral Proteins/genetics |
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