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

Abstract

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-κB. 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-κB 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-κB 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-κB signaling by API2·MALT1 was further questioned by RNA interference experiments. In contrast, TRAF6 was essential for NF-κB activation by all fusion variants, and we identified a novel TRAF6 binding site in the second immunoglobulin domain of MALT1, which enhanced NF-κB activation when present in the fusion protein. Furthermore, inclusion of both immunoglobulin domains in API2·MALT1 further enhanced NF-κB signaling via intramolecular TRAF6 activation. Finally, binding of TRAF2 to BIR1 contributed to NF-κB activation by API2·MALT1, although additional mechanisms involving BIR1-mediated raft association are also important. Taken together, these data reveal distinct mechanisms of NF-κB activation by the different API2·MALT1 fusion variants with an essential role for TRAF6. 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-κB. 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-κB 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-κB 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-κB signaling by API2·MALT1 was further questioned by RNA interference experiments. In contrast, TRAF6 was essential for NF-κB activation by all fusion variants, and we identified a novel TRAF6 binding site in the second immunoglobulin domain of MALT1, which enhanced NF-κB activation when present in the fusion protein. Furthermore, inclusion of both immunoglobulin domains in API2·MALT1 further enhanced NF-κB signaling via intramolecular TRAF6 activation. Finally, binding of TRAF2 to BIR1 contributed to NF-κB activation by API2·MALT1, although additional mechanisms involving BIR1-mediated raft association are also important. Taken together, these data reveal distinct mechanisms of NF-κB activation by the different API2·MALT1 fusion variants with an essential role for TRAF6. Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) 4The abbreviations used are: MALT, mucosa-associated lymphoid tissue; API2, apoptosis inhibitor-2; BCL10, B-cell CLL/lymphoma 10; BIR, baculovirus IAP repeat; DD, death domain; Ig, immunoglobulin; IκB, κB-inhibitory protein; IKK, IκB kinase; MEF, murine embryonic fibroblast; NF-κB, nuclear factor-κB; siRNA, small interfering RNA; TAK1, transforming growth factorβ-activated kinase-1; TAB, TAK1-binding protein; TRAF, tumor necrosis factor receptor-associated factor.4The abbreviations used are: MALT, mucosa-associated lymphoid tissue; API2, apoptosis inhibitor-2; BCL10, B-cell CLL/lymphoma 10; BIR, baculovirus IAP repeat; DD, death domain; Ig, immunoglobulin; IκB, κB-inhibitory protein; IKK, IκB kinase; MEF, murine embryonic fibroblast; NF-κB, nuclear factor-κB; siRNA, small interfering RNA; TAK1, transforming growth factorβ-activated kinase-1; TAB, TAK1-binding protein; TRAF, tumor necrosis factor receptor-associated factor. represents with 8% one of the most common types of non-Hodgkin B-cell lymphoma. Two translocations specific for MALT lymphoma are t(1,14)(p22; q32) and t(14,18)(q32;q21), which up-regulate the expression of the BCL10 and MALT1 gene, respectively, via their fusion to the enhancer of IgH (1Willis T.G. Jadayel D.M. Du M.Q. Peng H. Perry A.R. Abdul-Rauf M. Price H. Karran L. Majekodunmi O. Wlodarska I. Pan L. Crook T. Hamoudi R. Isaacson P.G. Dyer M.J. Cell. 1999; 96: 35-45Abstract Full Text Full Text PDF PubMed Scopus (568) Google Scholar, 2Zhang Q. Siebert R. Yan M. Hinzmann B. Cui X. Xue L. Rakestraw K.M. Naeve C.W. Beckmann G. Weisenburger D.D. Sanger W.G. Nowotny H. Vesely M. Callet-Bauchu E. Salles G. Dixit V.M. Rosenthal A. Schlegelberger B. Morris S.W. Nat. Genet. 1999; 22: 63-68Crossref PubMed Scopus (335) Google Scholar, 3Streubel B. Lamprecht A. Dierlamm J. Cerroni L. Stolte M. Ott G. Raderer M. Chott A. Blood. 2003; 101: 2335-2339Crossref PubMed Scopus (420) Google Scholar, 4Sanchez-Izquierdo D. Buchonnet G. Siebert R. Gascoyne R.D. Climent J. Karran L. Marin M. Blesa D. Horsman D. Rosenwald A. Staudt L.M. Albertson D.G. Du M.Q. Ye H. Marynen P. Garcia-Conde J. Pinkel D. Dyer M.J. Martinez-Climent J.A. Blood. 2003; 101: 4539-4546Crossref PubMed Scopus (181) Google Scholar). The most common genetic aberration is the translocation t(11;18)(q21;q21), where fusion of API2 to MALT1 results in the expression of an API2·MALT1 fusion protein (5Dierlamm J. Baens M. Wlodarska I. Stefanova-Ouzounova M. Hernandez J.M. Hossfeld D.K. Wolf-Peeters C. Hagemeijer A. Van den B.H. Marynen P. Blood. 1999; 93: 3601-3609Crossref PubMed Google Scholar). BCL10 (6Ruland J. Duncan G.S. Elia A. del B.B.I. Nguyen L. Plyte S. Millar D.G. Bouchard D. Wakeham A. Ohashi P.S. Mak T.W. Cell. 2001; 104: 33-42Abstract Full Text Full Text PDF PubMed Scopus (476) Google Scholar) and MALT1 (7Ruland J. Duncan G.S. Wakeham A. Mak T.W. Immunity. 2003; 19: 749-758Abstract Full Text Full Text PDF PubMed Scopus (299) Google Scholar, 8Ruefli-Brasse A.A. French D.M. Dixit V.M. Science. 2003; 302: 1581-1584Crossref PubMed Scopus (297) Google Scholar) play a crucial role in the signaling cascade from the antigen receptors to the transcription factor NF-κB. Upon T-cell receptor stimulation, CARMA1 (CARD-containing MAGUK protein-1) recruits the BCL10·MALT1·TRAF6 (9Gaide O. Favier B. Legler D.F. Bonnet D. Brissoni B. Valitutti S. Bron C. Tschopp J. Thome M. Nat. Immunol. 2002; 3: 836-843Crossref PubMed Scopus (292) Google Scholar, 10Che T. You Y. Wang D. Tanner M.J. Dixit V.M. Lin X. J. Biol. Chem. 2004; 279: 15870-15876Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar) and the IKK (11Stilo R. Liguoro D. Di Jeso B. Formisano S. Consiglio E. Leonardi A. Vito P. J. Biol. Chem. 2004; 279: 34323-34331Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar) (IKKα·IKKβ·IKKγ/NEMO) complexes to the lipid rafts (12Egawa T. Albrecht B. Favier B. Sunshine M.J. Mirchandani K. O'Brien W. Thome M. Littman D.R. Curr. Biol. 2003; 13: 1252-1258Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar, 13Hara H. Bakal C. Wada T. Bouchard D. Rottapel R. Saito T. Penninger J.M. J. Exp. Med. 2004; 200: 1167-1177Crossref PubMed Scopus (77) Google Scholar, 14Bidere N. Snow A.L. Sakai K. Zheng L. Lenardo M.J. Curr. Biol. 2006; 16: 1666-1671Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar) surrounding the receptor. Here it is thought that oligomerization of TRAF6 elicits its in of the of the IKK H. I. K. M. S. M. W. Dixit V.M. 2004; PubMed Scopus Google Scholar, L. L. Cell. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). with of by the L. L. Cell. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar) activates the IKK which and of the of NF-κB. In this NF-κB is a it to to the and its are of that the API2·MALT1 fusion protein a in the signaling to NF-κB. in that API2·MALT1 NF-κB M. N. L.M. S. M. G. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, K. S. Dixit V.M. Cell. Full Text Full Text PDF PubMed Google Scholar). this was to enhanced of in MALT H. Du M.Q. Dixit V.M. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar) and in M. S. X. H. S. Wolf-Peeters C. Marynen P. 2006; PubMed Scopus Google Scholar). is that the domains of API2 the oligomerization of the MALT1 which in TRAF6 oligomerization its However, the interaction of TRAF6 with MALT1 via the TRAF6 binding in its C terminus has been via and L. L. Cell. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, J. Biol. Cell. 2006; PubMed Scopus Google Scholar). a questioned a role for TRAF6 in NF-κB activation by API2·MALT1, the of both TRAF6 binding its signaling H. Du M.Q. Dixit V.M. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). In contrast, we a NF-κB activation for the TRAF6 binding site suggesting an essential role for TRAF6 in NF-κB signaling by API2·MALT1 M. S. X. H. S. Wolf-Peeters C. Marynen P. 2006; PubMed Scopus Google Scholar). API2·MALT1 fusion variants used in these H. Du M.Q. Dixit V.M. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, M. S. X. H. S. Wolf-Peeters C. Marynen P. 2006; PubMed Scopus Google which the In half of the MALT lymphoma with the API2·MALT1 protein contains the domains of API2 to the caspase-like domain of the the fusion variants in one immunoglobulin domains of MALT1, in and of the The domains interact with BCL10, which the enhanced NF-κB activation associated with fusion variants these domains K. S. Dixit V.M. Cell. Full Text Full Text PDF PubMed Google Scholar). In BCL10 was reported to interact with the first domain of API2 and to NF-κB with API2·MALT1 S. Du M.Q. A. L. S. J. Baens M. Ye H. Marynen P. X. J. 2006; PubMed Scopus Google Scholar). The first domain further with and although this interaction is in NF-κB activation by API2·MALT1 E. Dixit V.M. D. J. Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). the mechanisms by which API2·MALT1 activates NF-κB, we the role of BCL10, and TRAF6 for the different fusion variants. data a role for BCL10 in their NF-κB although TRAF2 via its interaction with the first domain of Furthermore, we an essential role for TRAF6 in NF-κB activation by all fusion variants and identified a TRAF6 binding site in the second domain of TRAF6 binding to NF-κB signaling by MALT1 and API2·MALT1 and to NF-κB activation by the API2·MALT1 fusion with both domains of MALT1 via intramolecular TRAF6 activation. expression of biotinylated was by the by D. E. 1999; PubMed Scopus Google Scholar) of the in the second the by a of the site used to for MALT1 and the API2·MALT1 fusion variants and of of API2 with and of MALT1, The of MALT1, and BCL10 by was to MALT1 with of of the TRAF6 binding and and which the to the different The was used to API2·MALT1 the binding site T. K. T. J.M. J. Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar) in their first The of the protein was from via and in the and MALT lymphoma in with in by with of by and with the and from a in with a of MALT1 and respectively, via their expression from a antigen receptor stimulation, with and for the with for in and with and and NF-κB The used for a of and for MALT1, a of and for BCL10, and a for protein in with the was and M. S. X. H. S. Wolf-Peeters C. Marynen P. 2006; PubMed Scopus Google Scholar). NF-κB M. S. X. H. S. Wolf-Peeters C. Marynen P. 2006; PubMed Scopus Google Scholar). and murine embryonic Van and M. in and with a of of to the The of of and of specific expression in of and the of to a of and was in a was the for to for in and is by E. P. E. J. E. A. J. S. A. 2003; PubMed Scopus Google Scholar). a protein of the biotinylated in via of the E. protein in for the biotinylated protein is via binding to streptavidin for in and for in a of and M. S. X. H. S. Wolf-Peeters C. Marynen P. 2006; PubMed Scopus Google Scholar). and protein complexes and to MALT1 and and MALT1 with with a the C terminus of MALT1 from used for of BCL10 TRAF6 and TRAF2 The and was from and NF-κB by API2·MALT1 API2·MALT1 fusion protein both domains of MALT1 a NF-κB in with the these domains K. S. Dixit V.M. Cell. Full Text Full Text PDF PubMed Google Scholar). In MALT1, the domains the interaction with BCL10, which is essential for MALT1 to NF-κB activation with BCL10 M. N. L.M. S. M. G. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). the in of the fusion variants to NF-κB with their to interact with BCL10, it was suggested that BCL10 to NF-κB signaling by the fusion via binding to its domains K. S. Dixit V.M. Cell. Full Text Full Text PDF PubMed Google Scholar). expression of API2·MALT1 with one both domains in in of the NF-κB with the and this with their to BCL10, we protein complexes from these API2·MALT1 fusion variants with a of the E. protein in this the of biotinylated API2·MALT1 with E. P. E. J. E. A. J. S. A. 2003; PubMed Scopus Google Scholar). of API2·MALT1 complexes showed an interaction with endogenous TRAF2 and TRAF6. endogenous BCL10 with of the fusion variants, in to the with a biotinylated MALT1 of the death domain in MALT1 its interaction with BCL10 BCL10 with the this suggested that the and the domains of MALT1 for BCL10 a we MALT lymphoma with expression of both the and and we TRAF2 and TRAF6 BCL10 in protein complexes RNA interference was used to the role of BCL10 in NF-κB activation by the fusion in BCL10 its expression in this the of the fusion to NF-κB. results for of MALT1, the NF-κB signaling by most of the of TRAF6 to MALT1 protein complexes the of a BCL10·MALT1·TRAF6 in and both in the of the antigen to NF-κB C and these data a role for BCL10 in NF-κB activation by the different API2·MALT1 fusion variants. TRAF6 for NF-κB protein complexes from and that the different API2·MALT1 fusion variants all interacted with TRAF2 and TRAF6 C and suggesting that both to the NF-κB of the Two TRAF6 binding identified in MALT1 MALT1 and MALT1 L. L. Cell. 2004; Full Text Full Text PDF PubMed Scopus Google of the most site to to NF-κB activation by M. S. X. H. S. Wolf-Peeters C. Marynen P. 2006; PubMed Scopus Google Scholar). complexes with the and in showed that the its to interact with TRAF6 and to the NF-κB the essential role of TRAF6 in NF-κB activation. report, questioned the involvement of TRAF6 in NF-κB signaling by API2·MALT1 of both and in NF-κB activation H. Du M.Q. Dixit V.M. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). the TRAF6 binding in the fusion variants one and we protein complexes with and their we a in NF-κB the binding of TRAF6 with suggesting an interaction the of TRAF6 binding site in the MALT1 the results for and in of the of the TRAF6 binding to we the second domain of MALT1 to in this additional interaction with TRAF6. of its TRAF6 binding of the MALT1 and MALT1 both in of MALT1 that of these the TRAF6 binding the of to NF-κB by suggesting an involvement in NF-κB signaling and of the with the the respectively, NF-κB activation by which with a of TRAF6 interaction and was reported that of the domain of MALT1 in an H. Du M.Q. Dixit V.M. Cell. Full Text Full Text PDF PubMed Scopus Google its interaction with and NF-κB suggesting a crucial role for binding of to this NF-κB activation by an we endogenous in the protein complexes from the different API2·MALT1 fusion variants that this the interaction of TRAF6 with the C terminus of also its to the binding which the NF-κB signaling. Finally, when the and in the of NF-κB activation these data that and interact with TRAF6 via distinct binding suggesting that their NF-κB in with from their to TRAF6 Furthermore, reveal that TRAF6 is essential for NF-κB activation by all API2·MALT1 fusion variants. TRAF6 to NF-κB of the novel TRAF6 binding site in the domain of MALT1 the this site is also in signaling to NF-κB. protein complexes with MALT1 an interaction with endogenous TRAF6 in and C and to and the interaction TRAF6 and MALT1 by the that MALT1 also contains TRAF6 binding and both in signaling to NF-κB, we the of their the of MALT1 with BCL10 for NF-κB activation. in of one of the TRAF6 binding in MALT1 the with BCL10, a of TRAF6 binding to MALT1 via the the of MALT1 and NF-κB activation to the of BCL10 expression In these data distinct TRAF6 binding in MALT1 that both to NF-κB signaling. for in NF-κB of MALT1 NF-κB activation although it activates NF-κB with BCL10 M. N. L.M. S. M. G. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google suggesting that BCL10 is for the oligomerization and activation of antigen receptor stimulation, this oligomerization is by the of the to the lipid rafts the which interaction with signaling and is essential for NF-κB activation. oligomerization in the experiments. in MALT1 is associated with the lipid raft in in to in the of MALT1 to the suggesting that BCL10 the oligomerization of in the lipid rafts in these for in NF-κB we showed a role for lipid rafts in NF-κB signaling by that of the first domain of API2 raft association of also NF-κB activation M. S. X. H. S. Wolf-Peeters C. Marynen P. 2006; PubMed Scopus Google Scholar). of BIR1 of and to the lipid rafts and although this for in a of NF-κB the of NF-κB the first domain contains a binding site T. K. T. J.M. J. Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus Google we its role in NF-κB signaling by all fusion variants. in the of the binding site in BIR1 the interaction of all fusion variants with endogenous TRAF2 and NF-κB activation by although it to NF-κB activation by and of showed that the the association of and with the lipid rafts which NF-κB raft association was also for the its interaction with TRAF6, which was for the BIR1 of and the in NF-κB signaling these data that lipid raft of all API2·MALT1 fusion variants is by the first domain of for and raft is associated with their to to NF-κB, NF-κB via an additional Furthermore, TRAF2 binding to BIR1 to NF-κB signaling by all fusion variants, although it is for their raft TRAF6 by the to and the BIR1 of NF-κB BIR1 is essential for raft in the also for oligomerization E. Dixit V.M. D. J. Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus Google this an additional and for NF-κB activation by In of the TRAF6 binding in MALT1, we questioned their fusion to API2 an intramolecular TRAF6 and activation in of a TRAF6 binding site NF-κB activation by although interaction of TRAF6 with the site was suggesting that an intramolecular TRAF6 activation to NF-κB signaling by In contrast, the for where of BIR1 NF-κB although both TRAF6 binding to TRAF6 In these data that intramolecular activation of TRAF6 to NF-κB signaling by NF-κB activation by the API2·MALT1 protein is essential for B-cell and of MALT is that of API2·MALT1 of and a role for the domain TRAF6 was L. L. Cell. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). report, suggested that API2·MALT1 NF-κB activation of TRAF6 and the to MALT1 H. I. K. M. S. M. W. Dixit V.M. 2004; PubMed Scopus Google Scholar, H. Du M.Q. Dixit V.M. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). and that API2 to to API2·MALT1 signaling E. Dixit V.M. D. J. Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). In contrast, BCL10 was reported to NF-κB with API2·MALT1 via its interaction with the first domain of API2 S. Du M.Q. A. L. S. J. Baens M. Ye H. Marynen P. X. J. 2006; PubMed Scopus Google Scholar). In this report, we the role of BCL10, and TRAF6 for NF-κB activation by different API2·MALT1 fusion variants. data that BCL10 interact with API2·MALT1 to its signaling to NF-κB. In contrast, all fusion variants one TRAF6 and we that this interaction is essential for NF-κB activation. Finally, TRAF2 also was to to NF-κB signaling by API2·MALT1. BCL10 and MALT1 crucial roles in the antigen receptor signaling to NF-κB activation (6Ruland J. Duncan G.S. Elia A. del B.B.I. Nguyen L. Plyte S. Millar D.G. Bouchard D. Wakeham A. Ohashi P.S. Mak T.W. Cell. 2001; 104: 33-42Abstract Full Text Full Text PDF PubMed Scopus (476) Google Scholar, J. Duncan G.S. Wakeham A. Mak T.W. Immunity. 2003; 19: 749-758Abstract Full Text Full Text PDF PubMed Scopus (299) Google Scholar, 8Ruefli-Brasse A.A. French D.M. Dixit V.M. Science. 2003; 302: 1581-1584Crossref PubMed Scopus (297) Google Scholar). role for BCL10 was also suggested in NF-κB an interaction BCL10 and the fusion variants via the domains of MALT1 the first domain of API2, K. S. Dixit V.M. Cell. Full Text Full Text PDF PubMed Google Scholar, S. Du M.Q. A. L. S. J. Baens M. Ye H. Marynen P. X. J. 2006; PubMed Scopus Google Scholar). However, we to the interaction all API2·MALT1 variants and endogenous BCL10, the results that Y. H. Y. R. M. 2004; PubMed Scopus Google Scholar) with an MALT1 the DD, the interact with endogenous BCL10 in to MALT1 and which that the with the domains of MALT1 for this via an its further that of BCL10 NF-κB signaling its involvement in this is further by the that the activates NF-κB to the in and (7Ruland J. Duncan G.S. Wakeham A. Mak T.W. Immunity. 2003; 19: 749-758Abstract Full Text Full Text PDF PubMed Scopus (299) Google Scholar). In contrast, S. Du M.Q. A. L. S. J. Baens M. Ye H. Marynen P. X. J. 2006; PubMed Scopus Google Scholar) reported that BCL10 to NF-κB in this the different types used to NF-κB activation by the API2·MALT1 fusion protein was to to enhanced of in H. Du M.Q. Dixit V.M. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar) and in MALT H. Du M.Q. Dixit V.M. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar) and of M. S. X. H. S. Wolf-Peeters C. Marynen P. 2006; PubMed Scopus Google Scholar). The of TRAF6 binding in the MALT1 C terminus a of the of TRAF6, although its interaction with MALT1 was by Here we that the fusion that the domains of MALT1 TRAF6 via its TRAF6 binding site which the of the its NF-κB signaling M. S. X. H. S. Wolf-Peeters C. Marynen P. 2006; PubMed Scopus Google Scholar). In contrast, fusion variants and which one both respectively, TRAF6 via an additional binding site of the second domain of TRAF6 binding to and signaling to NF-κB, of both is to NF-κB activation. of the TRAF6 binding the signaling associated with these variants. However, this to a that TRAF6 the of to NF-κB H. Du M.Q. Dixit V.M. Cell. Full Text Full Text PDF PubMed Scopus Google which of a of TRAF6 in these experiments. of TRAF6 NF-κB activation by the API2·MALT1 of by TRAF6 in an and an essential role for was of the domain in the MALT1 C terminus of both the interaction with and NF-κB activation H. Du M.Q. Dixit V.M. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). an interaction API2·MALT1 and endogenous we that a in TRAF6 binding and NF-κB of The interaction TRAF6 and J. L. M. Y. W. 2004; PubMed Scopus Google Scholar) an interaction of with MALT1 via TRAF6 a binding to its domain, further the essential role of TRAF6 for NF-κB activation by all fusion variants. binding TRAF6 complexes in and which was also suggested via J. Biol. Cell. 2006; PubMed Scopus Google Scholar). and of these complexes the rafts T-cell receptor their in is thought to an essential in T-cell receptor signaling to NF-κB T. You Y. Wang D. Tanner M.J. Dixit V.M. Lin X. J. Biol. Chem. 2004; 279: 15870-15876Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar, T. Albrecht B. Favier B. Sunshine M.J. Mirchandani K. O'Brien W. Thome M. Littman D.R. Curr. Biol. 2003; 13: 1252-1258Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar, 13Hara H. Bakal C. Wada T. Bouchard D. Rottapel R. Saito T. Penninger J.M. J. Exp. Med. 2004; 200: 1167-1177Crossref PubMed Scopus (77) Google Scholar, 14Bidere N. Snow A.L. Sakai K. Zheng L. Lenardo M.J. Curr. Biol. 2006; 16: 1666-1671Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar, J. Biol. Cell. 2006; PubMed Scopus Google Scholar). the interaction with the IKK it also TRAF6 and its in of and NF-κB activation. the TRAF6 binding site of the C terminus of MALT1 to the lipid rafts is to M. S. X. H. S. Wolf-Peeters C. Marynen P. 2006; PubMed Scopus Google Scholar). of MALT1 to the lipid rafts in of BCL10 is to its to NF-κB with BCL10 the also TRAF6 this further the raft association of MALT1 and TRAF6 raft association of the API2·MALT1 fusion was in of M. S. X. H. S. Wolf-Peeters C. Marynen P. 2006; PubMed Scopus Google Scholar) and in L. B. R. M. P. Staudt L.M. J. Blood. PubMed Scopus Google with and NF-κB that raft association of the in this antigen receptor signaling M. S. X. H. S. Wolf-Peeters C. Marynen P. 2006; PubMed Scopus Google Scholar). However, of which raft of the fusion protein M. S. X. H. S. Wolf-Peeters C. Marynen P. 2006; PubMed Scopus Google NF-κB signaling M. S. X. H. S. Wolf-Peeters C. Marynen P. 2006; PubMed Scopus Google Scholar) also TRAF6 binding to NF-κB signaling by of rafts via for a role of rafts in NF-κB signaling M. S. X. H. S. Wolf-Peeters C. Marynen P. 2006; PubMed Scopus Google Scholar). role was further by the BIR1 of and that also their raft to to the rafts NF-κB activation by the interaction with TRAF6. The NF-κB for the BIR1 for to an intramolecular TRAF6 activation the of TRAF6 binding for NF-κB activation. The of the BIR1 of to NF-κB it TRAF6 binding a a role for the first domain of MALT1 data that rafts play an role in NF-κB activation by all fusion variants, the signaling of for the binding site from raft association by to the domain of tumor necrosis factor receptor of which are reported to associated with rafts receptor D.F. O. Tschopp J. Bron C. Immunity. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). a of raft via also the in the rafts in to the BIR1 further the BIR1 NF-κB activation by the binding site Furthermore, BIR1 also to crucial for a oligomerization of the fusion in to the binding which also has been in NF-κB signaling by API2·MALT1 E. Dixit V.M. D. J. Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). In distinct mechanisms of NF-κB activation by the API2·MALT1 fusion that the domains contributed by the MALT1 protein of the second domain of MALT1 in the fusion protein NF-κB it additional TRAF6 binding of NF-κB signaling is by the first domain of MALT1 via an intramolecular TRAF6 activation Finally, the first domain of API2 the NF-κB of all fusion variants via its interaction with and a for their to the lipid raft of API2·MALT1 protein complexes and the of for this domain further the mechanisms by which API2·MALT1 to NF-κB. of for with and of for the