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胱天蛋白酶-8促进T细胞活化的机制。免疫应答的特征在于淋巴细胞的大量扩增以消除外来抗原，随后是大量凋亡以实现稳态。目前还不清楚如何凋亡机制是保持完整的增殖淋巴细胞，以确保其最终死亡。Caspase-8是一种对淋巴细胞凋亡起关键作用的启动子caspase。然而，最近的研究表明，自相矛盾的是，caspase-8也需要淋巴细胞增殖。胱天蛋白酶-8以潜伏形式（胱天蛋白酶原-8）产生，并且在细胞凋亡期间，其经历两个加工事件以产生成熟胱天蛋白酶-8。我们已经发现，这种激活是由半胱天冬酶原-8寡聚化引发的，并且涉及产生具有蛋白水解能力但与完全加工的成熟半胱天冬酶-8酶促不同的加工中间体。在淋巴细胞活化过程中，半胱氨酸天冬氨酸蛋白酶原-8与Bcl 10和MALT 1形成的复合物相关，两者都是抗原信号传导的关键介质。我们将1）建立在淋巴细胞增殖过程中控制半胱天冬酶原-8活化的机制，2）确定促进淋巴细胞增殖的半胱天冬酶原-8的形式，3）鉴定和表征半胱天冬酶-8增殖形式的底物。凋亡蛋白嵌入细胞增殖途径有效地连接了淋巴细胞生命和死亡的控制。因此，拟议的研究将揭示免疫中这两个基本细胞过程之间的相互作用，并将对基于半胱天冬酶的治疗免疫系统过度增殖和缺陷具有实际意义。

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.