A membrane-bound Fas decoy receptor expressed by human thymocytes
A membrane-bound Fas decoy receptor expressed by human thymocytes
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DOI：
10.1074/jbc.275.11.7988
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发表时间：
2000-03-17
影响因子：
4.8
通讯作者：
McCune, JM
中科院分区：
文献类型：
--
作者：
Jenkins, M;Keir, M;McCune, JM
处于不同成熟阶段的人胸腺细胞表达Fas，但不能通过Fas连接诱导细胞凋亡，这种抵抗与Fas诱导凋亡信号的近端步骤有关，由于这些细胞在肿瘤坏死因子-cu作用下经历了正常水平的凋亡诱导，我们研究了人胸腺细胞中表达的Fas受体，以探索受体介导的抑制这些细胞中Fas信号的机制。我们描述了一种独特的膜结合形式的Fas受体，它包含完整的Fas胞外结构域，但由于外显子7的选择性剪接而缺乏死亡结构域。这种Fas诱骗受体(FDR)被证明具有几乎野生型的结合天然人Fas配体的能力，并主要在质膜上表达。与可溶性形式的Fas受体不同，FDR主要抑制Fas配体诱导的人胚胎肾细胞的凋亡。Fas表达细胞中FDR的滴定表明，FDR可能通过形成混合受体复合体发挥作用。FDR还能明显抑制Fas诱导的Jurkat T细胞的凋亡。在与野生型Fas的混合实验中，FDR能够在摩尔比小于0.5时抑制死亡信号，并且至少在被测试的一些胸腺细胞中观察到这种相对水平的FDR：野生型信息。结果提示，Fas信号通路可能受膜结合的诱骗受体的调节，类似于诱骗受体对肿瘤坏死因子相关的凋亡诱导配体(TRAIL)诱导的细胞凋亡的调控。
Human thymocytes at several stages of maturation express Fas, yet resist apoptosis induction through its ligation, A proximal step in apoptotic signaling through Fas is implicated in this resistance, as these cells undergo normal levels of apoptosis induction after exposure to tumor necrosis factor-cu, We studied the Fas receptors expressed in human thymocytes to search for mechanisms of receptor-mediated inhibition of Fas signaling in these cells. We describe here a unique, membrane-bound form of Fas receptor that contained a complete extracellular domain of Fas but that lacked a death domain due to alternative splicing of exon 7. This Fas decoy receptor (FDR) was shown to have nearly wild-type ability to bind native human Fas ligand and was expressed predominantly at the plasma membrane. Unlike soluble forms of Fas receptor, FDR dominantly inhibited apoptosis induction by Fas ligand in transfected human embryonic kidney cells. Titration ofFDR in Fas-expressing cells suggests that FDR may operate through the formation of mixed receptor complexes. FDR also dominantly inhibited Fas-induced apoptosis in Jurkat T cells. In mixing experiments with wild-type Fas, FDR was capable of inhibiting death signaling at molar ratios less than 0.5, and this relative level of FDR: wild type message was observed in at least some thymocytes tested. The data suggest that Fas signal pathways in primary human cells may be regulated by expression of a membrane-bound decoy receptor, analogous to the regulation of tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-induced apoptosis by decoy receptors.