A novel TRAF6 binding site in MALT1 defines distinct mechanisms of NF-κB activation by API2•MALT1 fusions
A novel TRAF6 binding site in MALT1 defines distinct mechanisms of NF-κB activation by API2•MALT1 fusions
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DOI：
10.1074/jbc.m611038200
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发表时间：
2007-04-06
影响因子：
4.8
通讯作者：
Baens, Mathijs
中科院分区：
文献类型：
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作者：
Noels, Heidi;van Loo, Geert;Baens, Mathijs
与粘膜相关淋巴组织（MALT）淋巴瘤相关的复发性易位t（11;18）（q21; q21）导致API 2中心点MALT 1融合蛋白表达，该融合蛋白组成性激活NF-κ B。API 2的第一个杆状病毒IAP重复（BIR）结构域和MALT 1的C末端（包含其半胱天冬酶样结构域）存在于所有已报道的融合变体中，并分别与TRAF 2和TRAF 6相互作用，表明它们通过API 2中心点MALT 1对NF-κ B信号传导的贡献。此外，已经通过与API 2的BIR 1结合以及通过其与MALT 1的免疫球蛋白结构域的相互作用（存在于一半的融合变体中）提出了BCL 10的参与。然而，关于它们在API 2中心点MALT 1诱导的NF-κ B信号传导中的作用存在相互矛盾的报道。在本报告中，生物素化的API 2中心点MALT 1融合变体的链霉亲和素下拉显示，没有融合变体与内源性BCL 10相互作用;通过RNA干扰实验进一步质疑其在API 2中心点MALT 1的NF-κ B信号传导中的作用。相反，TRAF 6是所有融合变体激活NF-κ B所必需的，我们在MALT 1的第二免疫球蛋白结构域中鉴定了一个新的TRAF 6结合位点，当存在于融合蛋白中时，该位点增强NF-κ B激活。此外，在API 2中心点MALT 1中包含两个免疫球蛋白结构域进一步增强了通过分子内TRAF 6活化的NF-κ B信号传导。最后，TRAF 2与BIR 1的结合通过API 2中心点MALT 1促进NF-κ B活化，尽管涉及BIR 1介导的筏结合的其他机制也很重要。综上所述，这些数据揭示了不同的API 2中心点MALT 1融合变体激活NF-κ B的不同机制，这些变体对TRAF 6具有重要作用。
The recurrent translocation t(11;18)(q21; q21) associated with mucosa-associated lymphoid tissue (MALT) lymphoma results in the expression of an API2 center dot MALT1 fusion protein that constitutively activates NF-kappa 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-kappa B signaling by API2 center dot 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 center dot MALT1-induced NF-kappa B signaling. In this report, streptavidin pulldowns of biotinylated API2 center dot MALT1 fusion variants showed that none of the fusion variants interacted with endogenous BCL10; its role in NF-kappa B signaling by API2 center dot MALT1 was further questioned by RNA interference experiments. In contrast, TRAF6 was essential for NF-kappa B activation by all fusion variants, and we identified a novel TRAF6 binding site in the second immunoglobulin domain of MALT1, which enhanced NF-kappa B activation when present in the fusion protein. Furthermore, inclusion of both immunoglobulin domains in API2 center dot MALT1 further enhanced NF-kappa B signaling via intramolecular TRAF6 activation. Finally, binding of TRAF2 to BIR1 contributed to NF-kappa B activation by API2 center dot MALT1, although additional mechanisms involving BIR1-mediated raft association are also important. Taken together, these data reveal distinct mechanisms of NF-kappa B activation by the different API2 center dot MALT1 fusion variants with an essential role for TRAF6.