Sinha Suwan K, Chaudhary Preet M
Hamon Center for Therapeutic Oncology Research and the Division of Hematology-Oncology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8593, USA.
J Biol Chem. 2004 Oct 1;279(40):41873-81. doi: 10.1074/jbc.M407363200. Epub 2004 Jul 26.
X-linked ectodermal dysplasia receptor (XEDAR) is a recently isolated member of the tumor necrosis factor receptor family that is highly expressed during embryonic development and binds to ectodysplasin-A2 (EDA-A2). In this report, we demonstrate that although XEDAR lacks a death domain, it nevertheless induces apoptosis in an EDA-A2-dependent fashion. The apoptosis-inducing ability of XEDAR is dependent on the activation of caspase 8 and can be blocked by its genetic and pharmacological inhibitors. Although XEDAR-induced apoptosis can be blocked by dominant-negative Fas-associated death domain (FADD) protein and FADD small interfering RNA, XEDAR does not directly bind to FADD, tumor necrosis factor receptor-associated death domain (TRADD) protein, or RIP1. Instead, XEDAR signaling leads to the formation of a secondary complex containing FADD, caspase 8, and caspase 10, which results in caspase activation. Thus, XEDAR belongs to a novel class of death receptors that lack a discernible death domain but are capable of activating apoptosis in a caspase 8- and FADD-dependent fashion. XEDAR may represent an early stage in the evolution of death receptors prior to the emergence of the death domain and may play a role in the induction of apoptosis during embryonic development and adult life.
X连锁外胚层发育不良受体（XEDAR）是肿瘤坏死因子受体家族中最近分离出的成员，在胚胎发育过程中高度表达，并与外胚层发育不全蛋白A2（EDA-A2）结合。在本报告中，我们证明，尽管XEDAR缺乏死亡结构域，但它仍以EDA-A2依赖的方式诱导细胞凋亡。XEDAR的凋亡诱导能力依赖于半胱天冬酶8的激活，并可被其基因和药理学抑制剂阻断。虽然XEDAR诱导的细胞凋亡可被显性负性Fas相关死亡结构域（FADD）蛋白和FADD小干扰RNA阻断，但XEDAR并不直接与FADD、肿瘤坏死因子受体相关死亡结构域（TRADD）蛋白或RIP1结合。相反，XEDAR信号传导导致形成一个包含FADD、半胱天冬酶8和半胱天冬酶10的二级复合物，从而导致半胱天冬酶激活。因此，XEDAR属于一类新型的死亡受体，它们缺乏可识别的死亡结构域，但能够以半胱天冬酶8和FADD依赖的方式激活细胞凋亡。XEDAR可能代表死亡结构域出现之前死亡受体进化的早期阶段，并可能在胚胎发育和成年期的细胞凋亡诱导中发挥作用。
