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Antiapoptotic Function of Apoptosis Inhibitor 2-MALT1 Fusion Protein Involved in t(11;18)(q21;q21) Mucosa-Associated Lymphoid Tissue Lymphoma

¹ Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan, and ² Laboratory for Motor System Neurodegeneration, RIKEN Brain Science Institute, Wako City, Saitama, Japan

t(11;18)(q21;q21) is a characteristic chromosomal translocation in mucosa-associated lymphoid tissue (MALT) type lymphoma, and this translocation results in fusion transcript of apoptosis inhibitor 2 (API2), also known as c-IAP2, and MALT translocation gene 1 (MALT1). Although the API2-MALT1 fusion protein has been shown to enforce activation of nuclear factor B signaling, its precise role in the apoptotic signaling pathway remains to be established. To identify proteins that bind the API2-MALT1 protein, we used coimmunoprecipitation and SDS-PAGE, followed by liquid chromatography-electrospray ionization tandem mass spectrometry. As a result, three important regulators of apoptosis, Smac, HtrA2, and TRAF2, and three other proteins were identified as potential API2-MALT1-binding proteins. Immunoprecipitation analyses verified that API2-MALT1 indeed binds to both exogeneous and endogeneous Smac proteins. It is especially noteworthy that stably transfected API2-MALT1 significantly suppressed both UV- and etoposide-induced apoptosis in HeLa cells, thus demonstrating for the first time that API2-MALT1 indeed possesses antiapoptotic function. Furthermore, API2-MALT1 significantly suppressed Smac-promoted apoptosis in UV-irradiated HeLa cells. Thus, our results provide direct experimental evidence that API2-MALT1 can confer resistance to apoptosis, at least in part, by neutralizing apoptosis promoted by Smac.

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