Induction of apoptosis by X-linked ectodermal dysplasia receptor via a caspase 8-dependent mechanism.
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.
Sinha
Suwan K
SK
Hamon Center for Therapeutic Oncology Research and the Division of Hematology-Oncology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8593, USA.
Chaudhary
Preet M
PM
D017209:Apoptosis; D029681:Arabidopsis Proteins / Q000378:metabolism; D053455:Caspase 10; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D053331:Ectodysplasins; D053339:Edar Receptor; D004789:Enzyme Activation; D044943:Fatty Acid Desaturases / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins; D011485:Protein Binding; D053338:Receptors, Ectodysplasin; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D053340:Xedar Receptor
D029681:Arabidopsis Proteins; C506018:EDA protein, human; C506011:EDA2R protein, human; C506008:EDAR protein, human; D053331:Ectodysplasins; D053339:Edar Receptor; D008565:Membrane Proteins; D053338:Receptors, Ectodysplasin; D018124:Receptors, Tumor Necrosis Factor; D053340:Xedar Receptor; D044943:Fatty Acid Desaturases; C084083:Fad7 protein, Arabidopsis; C505530:CASP8 protein, human; D053455:Caspase 10; D053181:Caspase 8; D020169:Caspases; C506438:CASP10 protein, human