Cbl Mediated Ubiquitination in Autoimmunity

描述(由申请人提供)：自身反应性B细胞通过多种耐受诱导机制进行审查，包括克隆删除、无能(无反应性)或抗原受体编辑。一般认为，这些过程是通过B细胞抗原受体(BCR)和细胞因子受体的协调信号作用于骨髓(BM)未成熟和外周移行B细胞。然而，控制这些过程的细胞内信号机制还没有完全确定。这一建议的目的是阐明E3-泛素连接酶Cbl家族调节B细胞耐受的机制。本研究的目的在于：1)Cbl蛋白通过抑制酪氨酸激酶的级联反应，负向调节BCR信号转导。2)B细胞中c-Cbl和Cbl-b的失活改变了过渡性B细胞的发育。3)B细胞特异性c-Cbl和Cbl-b双基因敲除(DKO)小鼠发生系统性红斑狼疮(SLE)样疾病。这些结果共同证明了Cbl蛋白在B细胞耐受诱导中的关键调节作用。我们认为，Cbl蛋白通过促进克隆缺失、无能和/或bcr编辑来调节B细胞的耐受性；它们可能通过促进关键信号成分的泛素化来实现这一点，这些信号成分控制着对耐受诱导敏感的过渡性B细胞的发育和生存。我们将研究：1)Cbl蛋白是否通过克隆缺失、无能或BCR编辑来控制B细胞的耐受。2)Cb1蛋白是否在过渡性B细胞的发育检查点调节B细胞的耐受性。3)Cbl介导的泛素化是否控制BCR近端信号和过渡性B细胞的发育。这项工作的完成将深入了解Cbl蛋白控制B细胞耐受和自身免疫性疾病的细胞和分子机制。它也可能为临床治疗提供工具。

DESCRIPTION (provided by applicant): Autoreactive B cells are censored by multiple mechanisms of tolerance induction, including clonal deletion, anergy (non-responsiveness) or antigen receptor editing. It is generally believed that these processes are imposed to bone marrow (BM) immature and peripheral transitional B-cells through coordinated signaling of B-cell antigen receptor (BCR) and cytokine receptors. However, the intracellular signaling machinery that controls these processes has not been fully characterized. The aim of this proposal is to elucidate the mechanisms by which the Cbl family of E3-ubiquitin ligases regulates B-cell tolerance. This research goal roots in the following findings: 1) Cbl proteins negatively regulate BCR signaling through inhibiting tyrosine kinase cascades. 2) Inactivation of both c-Cbl and Cbl-b in B cells alters development of transitional B-cells. 3) B-cell specific c-Cbl and Cbl-b double knock-out (dKO) mice develop systemic lupus erythematosus (SLE)-like disease. These results together demonstrate a critical regulatory role of Cbl proteins in B-cell tolerance induction. We propose that Cbl proteins regulate B-cell tolerance by facilitating clonal deletion, anergy, and/or BCR editing; they may do so through promoting ubiquitination of key signaling components that control the development and survival of transitional B-cells that are susceptible to tolerance induction. We will study: 1) Whether Cbl proteins control B-cell tolerance through clonal deletion, anergy or BCR editing. 2) Whether Cbl proteins regulate B-cell tolerance at developmental checkpoints of transitional B-cells. 3) Whether Cbl-mediated ubiquitination controls BCR-proximal signaling and transitional B-cell development. Completion of this work will bring insight into cellular and molecular mechanisms by which Cbl proteins control B-cell tolerance and autoimmune diseases. It might also provide tool for clinic therapy.