Role of Caspase-8 in Lymphocyte Proliferation

描述(由申请人提供)：本提案的总体目标是阐明caspase-8促进T细胞激活的机制。免疫反应的特点是淋巴细胞大量扩张以清除外来抗原，随后大量凋亡以实现体内平衡。目前尚不清楚如何在增殖的淋巴细胞中保持凋亡机制的完好无损，以确保它们最终死亡。Caspase-8是一种在淋巴细胞凋亡中起关键作用的启动子。然而，最近的研究表明，矛盾的是，caspase-8也是淋巴细胞增殖所必需的。Caspase-8是以潜伏期形式(proaspase-8)形成的，在细胞凋亡过程中，它经历了两次加工过程才产生成熟的caspase-8。我们发现，这种激活是由proaspase-8寡聚触发的，涉及到产生加工中间体，这些加工中间体在蛋白质降解方面具有活性，但在酶学上不同于完全加工的成熟caspase-8。在淋巴细胞活化过程中，原天冬氨酸氨基转移酶-8与Bcl10和MALT1形成的复合体相关联，两者都是抗原信号的关键介质。我们将1)建立在淋巴细胞增殖过程中控制原天冬氨酸酶-8激活的机制，2)确定促进淋巴细胞增殖的原天冬氨酸酶-8的形式，以及3)鉴定和表征增殖形式的caspase-8的底物。在细胞增殖途径中嵌入凋亡蛋白，有效地控制了淋巴细胞的生死。因此，这项研究将对免疫中这两个基本细胞过程之间的相互作用提供重要的启示，并将对以caspase为基础的免疫系统过度增殖和缺陷的治疗具有实际意义。

DESCRIPTION (provided by applicant): The overall objective of this proposal is to elucidate the mechanism by which caspase-8 promotes T cell activation. Immune responses are characterized by massive expansion of lymphocytes to eliminate foreign antigens, followed by massive apoptosis to achieve homeostasis. It remains unclear how the apoptotic machinery is kept intact in proliferating lymphocytes to ensure their ultimate demise. Caspase-8 is an initiator caspase critical for lymphocyte apoptosis. However, recent studies indicate that paradoxically, caspase-8 is also required for lymphocyte proliferation. Caspase-8 is made in latent form (procaspase-8), and during apoptosis it undergoes two processing events to generate mature caspase-8. We have found that this activation is triggered by procaspase-8 oligomerization and involves the generation of processing intermediates that are proteolytically competent but enzymatically different from the fully processed mature caspase-8. During lymphocyte activation, procaspase-8 becomes associated with a complex formed by Bcl10 and MALT1, both being critical mediators of antigenic signaling. We will 1) establish the mechanism that controls procaspase-8 activation during lymphocyte proliferation, 2) determine the form of procaspase-8 that promotes lymphocyte proliferation, and 3) identify and characterize the substrates of the proliferative form of caspase-8. The embedment of an apoptotic protein into the cell proliferative pathway effectively links the control of lymphocyte life and death. The proposed study will thus shed important light on the interplay between these two fundamental cellular processes in immunity, and will have practical implications for caspase-based therapy for hyperproliferation and deficiency of the immune system.