1. TRAF2-binding BIR1 domain of c-IAP2/MALT1 fusion protein is essential for activation of NF-kappaB.
- Author
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Garrison JB, Samuel T, and Reed JC
- Subjects
- Apoptosis Regulatory Proteins genetics, Apoptosis Regulatory Proteins metabolism, Caspases chemistry, Caspases genetics, Cell Death drug effects, Cell Death genetics, Cells, Cultured, Cytokines pharmacology, Cytoprotection drug effects, Cytoprotection genetics, Drug Resistance, Neoplasm genetics, G Protein-Coupled Inwardly-Rectifying Potassium Channels metabolism, Humans, Inhibitor of Apoptosis Proteins chemistry, Inhibitor of Apoptosis Proteins genetics, Intracellular Signaling Peptides and Proteins metabolism, Jurkat Cells, Mitochondrial Proteins metabolism, Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein, Mutation physiology, Neoplasm Proteins chemistry, Neoplasm Proteins genetics, Oncogene Proteins, Fusion chemistry, Oncogene Proteins, Fusion metabolism, Oncogene Proteins, Fusion physiology, Protein Binding physiology, Protein Interaction Domains and Motifs genetics, TNF Receptor-Associated Factor 2 genetics, TNF Receptor-Associated Factor 2 physiology, Caspases metabolism, G Protein-Coupled Inwardly-Rectifying Potassium Channels chemistry, Inhibitor of Apoptosis Proteins metabolism, NF-kappa B metabolism, Neoplasm Proteins metabolism, TNF Receptor-Associated Factor 2 metabolism
- Abstract
Marginal zone mucosa-associated lymphoid tissue (MALT) B-cell lymphoma is the most common extranodal non-Hodgkin lymphoma. The t(11;18)(q21;q21) translocation occurs frequently in MALT lymphomas and creates a chimeric NF-kappaB-activating protein containing the baculoviral IAP repeat (BIR) domains of c-IAP2 (inhibitor of apoptosis protein 2) fused with portions of the MALT1 protein. The BIR1 domain of c-IAP2 interacts directly with TRAF2 (TNFalpha-receptor-associated factor-2), but its role in NF-kappaB activation is still unclear. Here, we investigated the role of TRAF2 in c-IAP2/MALT1-induced NF-kappaB activation. We show the BIR1 domain of c-IAP2 is essential for NF-kappaB activation, whereas BIR2 and BIR3 domains are not. Studies of c-IAP2/MALT1 BIR1 mutant (E47A/R48A) that fails to activate NF-kappaB showed loss of TRAF2 binding, but retention of TRAF6 binding, suggesting that interaction of c-IAP2/MALT1 with TRAF6 is insufficient for NF-kappaB induction. In addition, a dominant-negative TRAF2 mutant or downregulation of TRAF2 achieved by small interfering RNA inhibited NF-kappaB activation by c-IAP2/MALT1 showing that TRAF2 is indispensable. Comparisons of the bioactivity of intact c-IAP2/MALT1 oncoprotein and BIR1 E47A/R48A c-IAP2/MALT1 mutant that cannot bind TRAF2 in a lymphoid cell line provided evidence that TRAF2 interaction is critical for c-IAP2/MALT1-mediated increases in the NF-kappaB activity, increased expression of endogenous NF-kappaB target genes (c-FLIP, TRAF1), and resistance to apoptosis.
- Published
- 2009
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