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Functions of Bcl10 in Lymphocytes

Bcl10 在淋巴细胞中的功能

基本信息

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
项目类别：
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

项目摘要

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.

摘要