Glucose energy metabolism in the growth and survival of B lymphocytes

淋巴细胞使用相当多的能量来维持生存，支持生长和效应器功能，以响应抗原的挑战。葡萄糖能量代谢异常可能导致自身免疫性疾病和淋巴瘤。在过去的三十年里，B细胞抗原受体(BCR)在促进B细胞生长发育中的作用已经确立。很明显，共受体(如Ig G Fc受体、FcRIIB)可以负性调节Ag依赖和Ag非依赖的生长反应。FcRIIB基因缺失会导致自身抗体的产生和自身免疫性疾病，这突出了Fc RIIb在维持外周耐受方面的价值。Bcr和FcRIIB介导的淋巴细胞功能控制可能需要重新编程代谢；然而，几乎不知道这些受体的信号输入如何调节细胞代谢或这种调节的生物学意义。在这一点上，我们最近发现，BCR具有实时重新编程葡萄糖代谢的能力，以满足与B淋巴细胞激活相关的不断变化的生物能量和从头合成大分子的需求。这是通过依赖于磷脂酰肌醇3-激酶(PI-3K)的信号通路实现的，该信号针对参与从头开始脂肪形成(通过激活ATP柠檬酸裂解酶，ACL)和进入氧化戊糖磷酸途径(通过诱导葡萄糖6-磷酸脱氢酶(G6PD)基因表达)的几个关键限速酶，分别支持B细胞的生长和DNA复制。我们还发现了一条新的途径，将FcRIIB参与与糖酵解减少联系起来，这种反应与从哺乳动物细胞中移除生长因子导致细胞凋亡时观察到的糖酵解通量减少非常相似。我们的结果表明，FcRIIB参与后，限速糖酵解酶磷酸果糖激酶-1(Pfk-1)受到抑制。这项应用的中心目标是通过BCR和FcRIIB的信号输入来描述参与B淋巴细胞功能和生长反应的葡萄糖能量代谢的分子调控。拟议的研究将寻求测试两个具体目标。目的阐明BCR依赖的信号转导途径对前交叉韧带激活的分子调控。目的II阐明FcRIIB结合后糖酵解抑制的分子机制。从该项目收集的信息还将有助于提炼葡萄糖代谢失调如何导致B细胞反应异常，并可能确定代谢靶点，用于开发治疗某些以B细胞不受控制的扩张为特征的免疫疾病的方法。

Lymphocytes use considerable amounts of energy to maintain survival and to support growth and effector functions in response to antigen challenge. Aberrant glucose energy metabolism can contribute to autoimmune disease and lymphomas. During the past three decades the role of the B-cell antigen receptor (BCR) in promoting B-cell growth and development has been established. It is also clear that co-receptors (e.g., IgG Fc receptor, FcRIIB) can negatively modulate both Ag-dependent and Ag-independent growth responses. An appreciation for FcRIIB in the maintenance of peripheral tolerance is highlighted by the observation that its deletion can result in autoantibody production and autoimmune disease. BCR and FcRIIB mediated control of lymphocyte function likely requires re-programming of metabolism; however, virtually nothing is known about how signal input from these receptors modulate cellular metabolism or the biological significance of such regulation. On this point, we have recently discovered that the BCR possesses the capacity to reprogram glucose metabolism in real-time to meet the changing bioenergetic and de novo macromolecular synthetic demands associated with B lymphocyte activation. This is achieved by phosphatidylinositol 3-kinase (PI-3K)-dependent signaling that targets several essential rate-limiting enzymes involved in de novo lipogenesis (via activation of ATP citrate lyase, ACL), and entry into the oxidative pentose phosphate pathway (via induction of glucose 6-phosphate dehydrogenase (G6PD) gene expression) to support B-cell growth and DNA replication, respectively. We have also uncovered a novel pathway that links FcRIIB engagement to decreased glycolysis, a response remarkably similar to decreased glycolytic flux observed upon removal of growth factors from mammalian cells that leads to initiation of apoptosis. Our results suggest that the rate-limiting glycolytic enzyme, phosphofructokinase-1 (PFK-1) is inhibited following FcRIIB engagement. The central goal of this application is to delineate the molecular regulation of glucose energy metabolism involved in B lymphocyte function and growth responses by signal input from the BCR and FcRIIB. The proposed studies will seek to test two specific aims. Aim I will elucidate the molecular regulation of ACL activation with respect to BCR-dependent signaling. Aim II will elucidate the molecular mechanisms underlying inhibition of glycolysis following FcRIIB engagement. Information gathered from this project will also help to distill how dysregulation of glucose metabolism contributes to aberrant B-cell responses and may identify metabolic targets for the development of therapies to treat certain immune diseases characterized by uncontrolled expansion of B cells.