Inhibition of death receptor signals by cellular FLIP
Inhibition of death receptor signals by cellular FLIP
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DOI：
10.1038/40657
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发表时间：
1997-07-10
期刊：
影响因子：
64.8
通讯作者：
Tschopp, J
中科院分区：
文献类型：
--
作者：
Irmler, M;Thome, M;Tschopp, J
广泛表达的Fas蛋白是肿瘤坏死因子受体家族的成员，其可触发细胞凋亡（1）。然而，Fas表面表达并不一定使细胞对Fas配体诱导的死亡信号敏感（1，2），表明凋亡信号通路的抑制剂必须存在。在这里，我们报告的表征的细胞凋亡抑制剂，指定FLIP（FLICE抑制蛋白），这是主要在肌肉和淋巴组织中表达。短型FLIPS包含两个死亡效应结构域，并且在结构上与凋亡的病毒FLIP抑制剂相关（3），而长型FLIPL另外包含半胱天冬酶样结构域，其中活性中心半胱氨酸残基被酪氨酸残基取代。FLIPS和FLIPL与衔接蛋白FADD（4，5）和蛋白酶FLICE 6，7相互作用，并有效抑制所有已知的人类死亡受体诱导的细胞凋亡（1）。FLIPL在T细胞活化的早期阶段表达，但当T细胞变得对Fas配体介导的凋亡敏感时消失。在黑色素瘤细胞系和恶性黑色素瘤肿瘤中也可检测到高水平的FLIPL蛋白。因此，FLIP可能作为细胞凋亡的重要调节因子参与组织稳态。
The widely expressed protein Fas is a member of the tumour necrosis factor receptor family which fan trigger apoptosis(1). However, Fas surface expression does not necessarily render cells susceptible to Fas ligand-induced death signals(1,2), indicating that inhibitors of the apoptosis-signalling pathway must exist. Here we report the characterization of an inhibitor of apoptosis, designated FLIP (for FLICE-inhibitory protein), which is predominantly expressed in muscle and lymphoid tissues. The short form, FLIPS, contains two death effector domains and is structurally related to the viral FLIP inhibitors of apoptosis(3), whereas the long form, FLIPL, contains in addition a caspase-like domain in which the active-centre cysteine residue is substituted by a tyrosine residue. FLIPS and FLIPL interact with the adaptor protein FADD(4,5) and the protease FLICE6,7, and potently inhibit apoptosis induced by all known human death receptors(1). FLIPL is expressed during the early stage of T-cell activation, but disappears when T cells become susceptible to Fas ligand-mediated apoptosis. High levels of FLIPL protein are also detectable in melanoma cell lines and malignant melanoma tumours. Thus FLIP may be implicated in tissue homeostasis as an important regulator of apoptosis.