Glucose energy metabolism in the growth and survival of B lymphocytes

淋巴细胞使用大量的能量来维持存活并支持响应抗原攻击的生长和效应子功能。葡萄糖能量代谢异常可导致自身免疫性疾病和淋巴瘤。在过去的三十年中，B细胞抗原受体（BCR）在促进B细胞生长和发育中的作用已经确立。还清楚的是，共受体（例如，IgG Fc受体，Fc γ RIIB）可以负调节Ag依赖性和Ag非依赖性生长应答。通过观察到其缺失可导致自身抗体产生和自身免疫性疾病，强调了对Fc ECRIIIB在维持外周耐受性方面的评价。BCR和Fc γ RIIB介导的淋巴细胞功能控制可能需要重新编程代谢;然而，实际上对来自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一无所知。关于这一点，我们最近发现BCR具有实时重编程葡萄糖代谢的能力，以满足与B淋巴细胞活化相关的变化的生物能量和从头大分子合成需求。这是通过磷脂酰肌醇3-激酶（PI-3 K）依赖性信号传导实现的，该信号传导靶向参与从头脂肪生成（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（G6 PD）基因表达）的几种必需限速酶，以分别支持B细胞生长和DNA复制。我们还发现了一种新的途径，该途径将Fc γ RIIB接合与糖酵解减少联系起来，这一反应与从哺乳动物细胞中去除生长因子后观察到的糖酵解通量减少非常相似，从而导致细胞凋亡的启动。我们的研究结果表明，限速糖酵解酶，磷酸果糖激酶-1（PFK-1）被抑制后Fc γ RIIB的参与。本申请的中心目标是通过来自BCR和Fc γ RIIB的信号输入描述参与B淋巴细胞功能和生长应答的葡萄糖能量代谢的分子调节。拟议的研究将试图测试两个具体目标。目的阐明ACL激活与BCR依赖性信号的分子调控。目的II将阐明Fc γ RIIB结合后糖酵解抑制的分子机制。从该项目中收集的信息也将有助于提取葡萄糖代谢失调如何导致异常的B细胞反应，并可能确定代谢靶点，用于开发治疗某些以B细胞不受控制的扩增为特征的免疫疾病的疗法。

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.