Functions of Bcl10 in Lymphocytes

摘要 Bcl10(B细胞淋巴瘤10)是抗原受体介导的核因子B活化所必需的。在……里面 小鼠，Bcl10缺乏会导致淋巴细胞发育和增殖缺陷，以及 抑制免疫反应；而在人类中，涉及Bcl10的染色体易位是 与淋巴瘤的发展有关。在与T细胞受体Bcl10结合时 与适配器蛋白MALT1一起从胞浆转位，并与 脂筏中的脂类CARMA1。随后，CARMA1/Bcl10/MALT1复合体招募 B-激活激酶与脂筏结合，导致转录因子NF-954；B的激活。 我们和其他人最近的研究表明，TCR参与导致了Bcl10 核因子B活性的降解和下调。然而，Bcl10通过的机制 已经退化，这一事件的生物后果在很大程度上是难以捉摸的。我们最近有一次 报道S138是Bcl10上的一个激活依赖的磷酸化位点，并证明了 用稳定的BCl10丙氨酸残基取代S138，延长了核因子-B的活性和 增强T细胞产生IL-2的能力。此外，最近的一项研究报告称，TCR参与度 导致Bcl10被MALT1切割产生Bcl10短形式，这对T 细胞黏附。我们观察到用丙氨酸残基取代S138似乎是稳定的 全长Bcl10，但导致短型Bcl10的消失。此外，我们 结果显示，溶酶体酶抑制剂稳定了全长Bcl10，而 蛋白酶体抑制剂导致短型Bcl10的积累。因此，我们建议 Bcl10在S138上的磷酸化通过靶向全长Bcl10的降解 溶酶体途径，以及Bcl10短型的信号产生，然后被降解 通过蛋白酶体依赖的途径。其分子机制 Bcl10上S138的磷酸化引导全长Bcl10和短型Bcl10的降解 产生和降解，S138磷酸化的生物学后果是 在细胞系和动物系统中进行了研究。拟议的研究应该导致一个 提高对Bcl10调节核因子B依赖信号的机制的理解 转导，阐明了广泛的免疫学和 炎症性疾病，并为设计治疗药物提供重要的新见解 以控制或治愈这些疾病为目标。

ABSTRACT Bcl10 (B-cell lymphoma 10) is essential for antigen receptor mediated NF-κB activation. In mice, Bcl10 deficiency results in defective lymphocyte development and proliferation, and dampened immune responses; while in humans, chromosomal translocation involving Bcl10 is associated with the development of lymphoma. Upon engagement of the T cell receptor, Bcl10 translocates with the adaptor protein MALT1, from the cytosol and becomes associated with the lipid CARMA1 in the lipid rafts. Subsequently, the CARMA1/Bcl10/MALT1 complex recruits the IκB-activating kinase to the lipid rafts, resulting in activation of the transcription factor NF-κB. Recent studies by us and others have shown that TCR engagement resulted in Bcl10 degradation and down-regulation of NF-κB activation. However, the mechanism by which Bcl10 is degraded and the biological consequences of this event are largely elusive. We recently have reported S138 as an activation dependent phosphorylation site on Bcl10 and demonstrated that substitution of S138 with alanine residue stabilized Bcl10, prolonged NF-κB activation and enhanced IL-2 production by T cells. In addition, a recent study reported that TCR engagement resulted in cleavage of Bcl10 by MALT1 to generate a Bcl10 short-form, which is important for T cell adhesion. We observed that substitution of S138 with alanine residue appeared to stabilize full-length Bcl10 but resulted in the disappearance of the short-form Bcl10. In addition, we showed that a lysosomal enzyme inhibitor stabilized the full-length Bcl10, whereas a proteasome inhibitor resulted in the accumulation of short-form Bcl10. We thus propose that phosphorylation of Bcl10 on S138 targets full-length Bcl10 degradation through lysosome pathway, and signals generation of Bcl10 short-form, which is then degraded through proteasome-dependent pathway. The molecular mechanisms by which phosphorylation of S138 on Bcl10 directs full-length Bcl10 degradation and short-form Bcl10 generation and degradation, and the biological consequences of S138 phosphorylation will be investigated in both cell line and animal systems. The proposed research should lead to an improved understanding of the mechanisms by which Bcl10 regulates NF-κB-dependent signal transduction, shed light on the molecular pathogenesis of a wide range of immunological and inflammatory disorders, and provide important new insights for designing therapeutic drugs targeted at controlling or curing these disorders.