Yu J W, Shi Y
Department of Molecular Biology, Lewis Thomas Laboratory, Princeton University, Princeton, NJ, 08544 USA.
Oncogene. 2008 Oct 20;27(48):6216-27. doi: 10.1038/onc.2008.299.
Death effector domains (DEDs) are protein interaction modules found in a number of proteins known to regulate apoptosis from death receptors. The core DED family members that orchestrate programmed cell death from death receptors include the adaptor protein FADD, the initiator caspases procaspases-8 and -10 and the regulatory protein c-FLIP. Through homotypic DED interactions, these proteins assemble into the death-inducing signaling complex (DISC) to regulate initiator caspase activation and launch the apoptotic proteolytic cascade. A considerable body of evidence, however, is revealing that the same core group of DED-containing proteins also paradoxically promotes survival and proliferation in lymphocytes and possibly other cell types. This review delves into recent findings regarding these two opposing functional aspects of the core DED proteins. We discuss the current effort expanding our structural and biochemical view of how DED proteins assemble into the DISC to fully activate initiator caspases and execute cell death, and finally we examine details linking the same proteins to proliferation and describe how this outcome might be achieved through restricted activation of initiator caspases.
死亡效应结构域（DEDs）是在许多已知可调节死亡受体介导的细胞凋亡的蛋白质中发现的蛋白质相互作用模块。协调死亡受体介导的程序性细胞死亡的核心DED家族成员包括衔接蛋白FADD、起始半胱天冬酶原半胱天冬酶-8和-10以及调节蛋白c-FLIP。通过同型DED相互作用，这些蛋白质组装成死亡诱导信号复合物（DISC），以调节起始半胱天冬酶的激活并启动凋亡蛋白水解级联反应。然而，大量证据表明，同一组含核心DED的蛋白质在淋巴细胞以及可能的其他细胞类型中也反常地促进存活和增殖。本综述深入探讨了有关核心DED蛋白这两个相反功能方面的最新发现。我们讨论了当前为扩展我们对DED蛋白如何组装成DISC以完全激活起始半胱天冬酶并执行细胞死亡的结构和生化观点所做的努力，最后我们研究了将相同蛋白质与增殖联系起来的细节，并描述了如何通过起始半胱天冬酶的受限激活来实现这一结果。
