Abstract
Mucosa-associated lymphoid tissue (MALT) lymphomais the most common extranodal lymphoid neoplasm. Chromosomal translocation t(11;18)(q21,q21) is found in 30% of gastric MALT lymphomas and is associated with a failure to respond to standard treatment and a tendency to disseminate. This translocation generates a chimeric protein composed of N-terminal sequences of Inhibitor of Apoptosis 2 (API2, also known as BIRC3 and cIAP2) fused to C-terminal sequences of MALT1. API2-MALT1 promotes cell survival and proliferation via activation of nuclear factor-κB (NF-κB). Here, we investigate the mechanism by which the API2 moiety contributes to NF-κB stimulation. We find that the API2 moiety mediates oligomerization of API2-MALT1 as well as interaction with tumor necrosis factor receptor-associated factor 2 (TRAF2). Surprisingly, oligomerization does not occur via homotypic interaction; rather, the API2 moiety of one monomer interacts with the MALT1 moiety of another monomer. Further, the specific region of the API2 moiety responsible for mediating oligomerization is distinct from that mediating TRAF2 binding. Although deletion or mutation of the TRAF2 binding site does not inhibit oligomerization, it does lead to dramatically decreased NF-κB activation. Deletion of both TRAF2 binding and oligomerization regions results in near-complete loss of NF-κB activation. Thus, API2 moiety-mediated heterotypic oligomerization and TRAF2 binding both contribute to maximal API2-MALT1-dependent NF-κB stimulation.
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Acknowledgements
We thank Dr Gabriel Nunez for helpful discussion and valuable reagents. PCL and LMML are recipients of NIH KO8 awards (5KO8 CA097986 and 5KO8 CA094920, respectively). LMML is also a recipient of a Doris Duke Clinical Scientist Development Award. This project was partially supported by a grant from the Children's Health Research Center (CHRC) and the Shirley K Schlafer Foundation.
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Lucas, P., Kuffa, P., Gu, S. et al. A dual role for the API2 moiety in API2-MALT1-dependent NF-κB activation: heterotypic oligomerization and TRAF2 recruitment. Oncogene 26, 5643–5654 (2007). https://doi.org/10.1038/sj.onc.1210342
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DOI: https://doi.org/10.1038/sj.onc.1210342
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