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J. Biol. Chem., Vol. 282, Issue 14, 10180-10189, April 6, 2007

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A Novel TRAF6 Binding Site in MALT1 Defines Distinct Mechanisms of NF-B Activation by API2·MALT1 Fusions^*

Heidi Noels¹, Geert van Loo^¶||2, Sofie Hagens, Vicky Broeckx, Rudi Beyaert^¶||, Peter Marynen, and Mathijs Baens³

From the Human Genome Laboratory, Department for Molecular and Developmental Genetics, Flanders Institute for Biotechnology (VIB), B-3000 Leuven, Belgium, the Human Genome Laboratory, Molecular Genetics, Center for Human Genetics, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium, the ^¶Unit of Molecular Signal Transduction in Inflammation, Department for Molecular Biomedical Research, Flanders Institute for Biotechnology (VIB), B-9052 Ghent, Belgium, and the ^||Unit of Molecular Signal Transduction in Inflammation, Department of Molecular Biology, Ghent University, B-9052 Ghent, Belgium

The recurrent translocation t(11;18)(q21;q21) associated with mucosa-associated lymphoid tissue (MALT) lymphoma results in the expression of an API2·MALT1 fusion protein that constitutively activates NF-B. The first baculovirus IAP repeat (BIR) domain of API2 and the C terminus of MALT1, which contains its caspase-like domain, are present in all reported fusion variants and interact with TRAF2 and TRAF6, respectively, suggesting their contribution to NF-B signaling by API2·MALT1. Also, the involvement of BCL10 has been suggested via binding to BIR1 of API2 and via its interaction with the immunoglobulin domains of MALT1, present in half of the fusion variants. However, conflicting reports exist concerning their roles in API2·MALT1-induced NF-B signaling. In this report, streptavidin pulldowns of biotinylated API2·MALT1 fusion variants showed that none of the fusion variants interacted with endogenous BCL10; its role in NF-B signaling by API2·MALT1 was further questioned by RNA interference experiments. In contrast, TRAF6 was essential for NF-B activation by all fusion variants, and we identified a novel TRAF6 binding site in the second immunoglobulin domain of MALT1, which enhanced NF-B activation when present in the fusion protein. Furthermore, inclusion of both immunoglobulin domains in API2·MALT1 further enhanced NF-B signaling via intramolecular TRAF6 activation. Finally, binding of TRAF2 to BIR1 contributed to NF-B activation by API2·MALT1, although additional mechanisms involving BIR1-mediated raft association are also important. Taken together, these data reveal distinct mechanisms of NF-B activation by the different API2·MALT1 fusion variants with an essential role for TRAF6.

Received for publication, November 30, 2006 , and in revised form, January 23, 2007.

^* This work was supported by Grants SCIE2003-09 from the "Belgische Federatie tegen Kanker" and 04-149 from the Association for International Cancer Research (to P. M.); by Grants 3G010505 from the Fonds voor Wetenschappelijk Onderzoek (FWO)-Vlaanderen and 01G06B6 from the Fonds "Geconcerteerde Onderzoeksacties" (to R. B.); and by the IAP6/18 network (to R. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ An aspirant with FWO-Vlaanderen.

² Postdoctoral research fellow with FWO-Vlaanderen.

³ To whom correspondence should be addressed: Human Genome Laboratory, Center for Human Genetics, Molecular Genetics, K.U. Leuven, Herestraat 49, B3000 Leuven, Belgium. Tel.: 32-16-33-01-30; Fax: 32-16-34-71-66; E-mail: Mathijs.Baens{at}Med.KULeuven.be.

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