CbI mediated ubiquitination in autoimmunity Systemic Lupus Erythematosus (SLE)

描述（由申请人提供）：自身反应性B细胞受到多种耐受性诱导机制的抑制，包括克隆缺失、能量（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传导作用于骨髓（BM）未成熟和外周移行性b细胞。然而，控制这些过程的细胞内信号机制尚未得到充分表征。本研究旨在阐明b3 -泛素连接酶的Cbl家族调控b细胞耐受性的机制。本研究的目的源于以下发现：1)Cbl蛋白通过抑制酪氨酸激酶级联负调控BCR信号。2) B细胞中c-Cbl和Cbl-b的失活改变了移行性B细胞的发育。3) b细胞特异性c-Cbl和Cbl-b双敲除（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细胞耐受性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、能量和/或BCR编辑来调节b细胞的耐受性；它们可能通过促进控制易受耐受性诱导的过渡性b细胞发育和存活的关键信号成分的泛素化来实现这一目标。我们将研究：1)Cbl蛋白是否通过克隆缺失、能量或BCR编辑来控制b细胞耐受性。2) Cbl蛋白是否在过渡性b细胞发育检查点调控b细胞耐受性。3) cbl介导的泛素化是否控制bcr -近端信号传导和移行性b细胞发育。这项工作的完成将使我们深入了解Cbl蛋白控制b细胞耐受性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.