TRAF2-binding BIR1 domain of c-IAP2/MALT1 fusion protein is essential for activation of NF-kappaB.
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.
Garrison
J B
JB
Program on Apoptosis and Cell Death Research, Cancer Center, Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
Samuel
T
T
Reed
J C
JC
D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D020169:Caspases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D019610:Cytoprotection / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D019169:Jurkat Cells; D024101:Mitochondrial Proteins / Q000378:metabolism; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D009154:Mutation / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000737:chemistry / Q000378:metabolism / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D054730:Protein Interaction Domains and Motifs / Q000235:genetics; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology
D051017:Apoptosis Regulatory Proteins; D016207:Cytokines; C412403:DIABLO protein, human; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; C094401:KCNJ6 protein, human; D024101:Mitochondrial Proteins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D047992:TNF Receptor-Associated Factor 2; D020169:Caspases; C400109:MALT1 protein, human; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein