Functions of Bcl10 in Lymphocytes

Bcl10 在淋巴细胞中的功能

• 批准号: 7929077
• 负责人: Renren Wen
• 金额: $ 40.75万
• 依托单位: VERSITI WISCONSIN, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-23 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7929077
• 关键词: Adaptor Signaling Protein; Address; Affect; Alanine; Animals; Antigen Receptors; Arginine; B-Cell Lymphomas; B-Lymphocytes; Biochemical; Biological; Biological Process; Biological Testing; Bone Marrow Transplantation; Cell Adhesion; Cell Line; Cells; Chromosomal translocation; Complex; Cytosol; Data; Development; Dimerization; Disease; Down-Regulation; Drug Delivery Systems; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Event; Gene Transfer; Generations; Grant; Human; Immune response; Immunologic Deficiency Syndromes; Inflammation; Inflammatory; Interleukin-2; Knock-in Mouse; Lead; Length; Light; Lipids; Lymphocyte; Lymphocyte Activation; Lymphoma; Lysosomes; MG132; Mediating; Membrane Microdomains; Molecular; Molecular Abnormality; Mus; Pathogenesis; Pathway interactions; Phosphorylation; Phosphorylation Site; Phosphotransferases; Play; Production; Proteasome Inhibitor; Proteins; Recruitment Activity; Reporting; Research; Retroviridae; Role; Signal Pathway; Signal Transduction; System; T-Cell Development; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Transgenic Organisms; Ubiquitination; Vesicle; abstracting; antigen challenge; base; cytokine; design; functional outcomes; human disease; improved; in vivo; insight; mucosa-associated lymphoid tissue lymphoma; multicatalytic endopeptidase complex; mutant; prevent; response; transcription factor; tumor; ubiquitin-protein ligase

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.

抽象的 Bcl10（B细胞淋巴瘤10）对于抗原受体介导的NF-κB激活至关重要。在 小鼠，Bcl10缺乏会导致淋巴细胞的发育和增殖，以及 抑制免疫反应；在人类中，涉及Bcl10的染色体易位为 与淋巴瘤的发展有关。 T细胞受体参与后Bcl10 与辅助蛋白Malt1易位，从细胞质中易位，并与 脂质筏中的脂质carma1。随后，Carma1/bcl10/Malt1复合物招募了 IκB激活激酶向脂质筏，导致转录因子NF-κB的激活。 我们和其他人最近的研究表明，TCR参与导致BCL10 NF-κB激活的降解和下调。但是，bcl10的机制 被降解，此事件的生物学后果在很大程度上难以捉摸。我们最近有 报道了S138作为Bcl10上的激活依赖性磷酸化位点，并证明 用丙氨酸残基稳定Bcl10，长时间NF-κB激活和替代S138 T细胞增强了IL-2的产生。此外，最近的一项研究报道了TCR参与 导致MALT1裂解Bcl10以生成Bcl10短形式，这对于t很重要 细胞粘附。我们观察到用丙氨酸残基的S138取代似乎稳定 全长Bcl10，但导致短形式BCl10消失。另外，我们 表明溶酶体酶抑制剂稳定了全长Bcl10，而A 蛋白酶体抑制剂导致较短的Bcl10的积累。因此，我们建议 BCl10在S138上的磷酸化靶向全长Bcl10通过 溶酶体途径和信号生成Bcl10短形式，然后将其降解 通过蛋白酶体依赖性途径。分子机制 BCl10上S138的磷酸化指导全长Bcl10降解和短形式BCl10 生成和降解以及S138磷酸化的生物学后果将是 在细胞系和动物系统中进行了研究。拟议的研究应导致 对BCL10调节NF-κB依赖性信号的机制的了解得以提高 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 针对控制或治愈这些疾病。