Functions of Bcl10 in Lymphocytes

摘要 Bcl 10（B细胞淋巴瘤10）对于抗原受体介导的NF-B活化是必需的。在 在小鼠中，Bcl 10缺乏导致淋巴细胞发育和增殖缺陷， 抑制免疫反应;而在人类中，涉及Bcl 10的染色体易位， 与淋巴瘤的发展有关。在T细胞受体Bcl 10的参与下， 与衔接蛋白MALT 1易位，从胞质溶胶，并成为相关的 脂质筏中的脂质CARMA 1。随后，CARMA 1/Bcl 10/MALT 1复合物招募了 I B激活激酶与脂筏结合，导致转录因子NF- B的激活。 我们和其他人最近的研究表明，TCR参与导致Bcl 10 NF- B活化的降解和下调。然而，Bcl 10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 报道了S138作为Bcl 10上的活化依赖性磷酸化位点，并证明， 用丙氨酸残基取代S138稳定了Bcl 10，延长了NF-B活化， 增强T细胞的IL-2产生。此外，最近的一项研究报告称，TCR参与 导致Bcl 10被MALT 1切割产生Bcl 10短形式，这对T 细胞粘附我们观察到用丙氨酸残基取代S138似乎稳定了 全长Bcl 10，但导致短型Bcl 10的消失。另外我们 显示溶酶体酶抑制剂稳定全长Bcl 10，而溶酶体酶抑制剂稳定全长Bcl 10。 蛋白酶体抑制剂导致短型Bcl 10的积累。因此，我们建议， S138上Bcl 10的磷酸化通过以下途径靶向全长Bcl 10降解： 溶酶体途径，并信号产生Bcl 10短形式，然后降解 通过蛋白酶体依赖的途径。的分子机制 Bcl 10上S138的磷酸化指导全长Bcl 10降解和短形式Bcl 10 产生和降解，S138磷酸化的生物学后果将是 在细胞系和动物系统中研究。拟议的研究应导致 提高对Bcl 10调节NF-B依赖性信号的机制的理解 转导，揭示了广泛的免疫和 炎症性疾病，并为设计治疗药物提供重要的新见解 旨在控制或治愈这些疾病。

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.