Molecular elucidation of the CBM complex in NF-kappaB activation by antigen recep

描述（由申请人提供）：NF-kB信号在调节适应性免疫反应中淋巴细胞的激活、增殖和效应功能方面起着至关重要的作用。这一过程的放松会导致免疫缺陷、自身免疫性疾病或肿瘤疾病。在其他共刺激信号存在的情况下，NF-kB通过TCR与mhc结合抗原肽的结合或BCR与抗原的相互作用而被激活。蛋白激酶C ？在抗原受体触发过程中，t细胞的PKC?和b细胞的PKC?被募集到脂质筏中，并分别在TCR和bcr诱导的NF-kB激活中发挥关键作用。CARMA1 [caspase-募集结构域（CARD）膜相关鸟苷酸激酶（MAGUK）蛋白1，也称为CARD11]、Bcl10 （b细胞淋巴瘤10）和MALT1（粘膜相关淋巴组织淋巴瘤易位蛋白1）的三元复合物作用于PKC的下游。和PKC¿诱导B和T淋巴细胞中IkB激酶（IKK）的激活（图1）。CARMA1似乎与细胞质膜结构相关。在TCR刺激下，CARMA1被重新分配到免疫突触的脂质筏中，招募Bcl10和MALT1形成CARMA1-Bcl10-MALT1 （CBM）复合物。目前还没有关于CBM复合物或其组成蛋白的结构信息。此外，尽管CARMA1、Bcl10和MALT1具有属于已知蛋白家族的结构域，但它们与任何已知蛋白的序列同源性非常有限。为了填补这一空白，我们建议对CBM复合物进行完整的综合结构分析，包括其组装机制，构象变化，酶活性和翻译后修饰。这些研究将不可避免地提供对这一重要信号复合物的深入了解。

DESCRIPTION (provided by applicant): NF-kB signaling has a crucial role in regulating the activation, proliferation and effector functions of lymphocytes in adaptive immune responses. Deregulation of this process results in immunodeficiency, autoimmune diseases, or neoplastic disorders. In the presence of additional co-stimulatory signals, NF-kB is activated by the engagement of TCR with MHC-bound antigen peptides or the interaction of BCR with antigens. The protein kinase C ? (PKC?) of T-cells and PKC¿ of B-cells are recruited to lipid rafts during antigen-receptor triggering and play key roles in TCR- and BCR-induced NF-kB activation, respectively. The ternary complex of CARMA1 [caspase-recruitment domain (CARD) membrane-associated guanylate kinase (MAGUK) protein 1, also known as CARD11], Bcl10 (B-cell lymphoma 10) and MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) acts downstream of PKC? and PKC¿ to induced activation of the IkB kinase (IKK) in both B and T lymphocytes (Figure 1). CARMA1 appears to be constitutively associated with the cytoplasmic membrane. Upon TCR stimulation, CARMA1 is redistributed to the lipid rafts at the immunological synapse to recruit Bcl10 and MALT1 to form the CARMA1-Bcl10-MALT1 (CBM) complex. No structural information is currently available on the CBM complex or its component proteins. In addition, despite having domains that belong to known protein families, CARMA1, Bcl10 and MALT1 exhibit very limited sequence homology to any of the known proteins. To fill this gap, we propose a complete comprehensive structural analysis on the CBM complex, including its assembly mechanisms, conformational changes, enzymatic activities and post-translational modifications. These studies will inevitably provide insights into this important signaling complex. PUBLIC HEALTH RELEVANCE: The proteins in the CBM complex play critical roles in Non-Hodgkin's lymphomas and may be bona fide oncogenes. CARMA1 overexpression has been found in adult T-cell leukemia, primary gastric B-cell lymphoma, and diffuse large B-cell lymphoma (DLBCL). In DLBCL, the most common form of non-Hodgkin's lymphoma, missense mutations of CARMA1 have been found at the coiled coil region of CARMA1, which correlate with constitutive NF-kB activation. Chromosomal translocations of both Bcl10 and MALT1 have been found in mucosa-associated lymphoid tissue (MALT) lymphoma. The most frequent chromosomal aberrations in MALT lymphoma are the t(11;18)(q21:q21) and t(14;18)(q32:q21) translocations, which account for about half of all MALT lymphoma. The former translocation creates a fusion protein comprising the BIR domains of cIAP2 and the meta-caspase domain of MALT1 and constitutive NF-kB activation. The t(14;18) translocation results in positioning of the MALT1 genes to the Ig heavy chain locus. Similarly for Bcl10, the t(1;14)(p22:q32) translocation places the Bcl10 to the Ig heavy chain locus. These translocations likely activate NF-kB through MALT1 and Bcl10 overexpression. Collectively, these studies suggest that the CBM complex is an attractive therapeutic target neoplastic disorders of the lymphocytes.