Irmler M, Thome M, Hahne M, Schneider P, Hofmann K, Steiner V, Bodmer J L, Schröter M, Burns K, Mattmann C, Rimoldi D, French L E, Tschopp J
Institute of Biochemistry, Lausanne branch, University of Lausanne, Switzerland.
Nature. 1997 Jul 10;388(6638):190-5. doi: 10.1038/40657.
The widely expressed protein Fas is a member of the tumour necrosis factor receptor family which can trigger apoptosis. However, Fas surface expression does not necessarily render cells susceptible to Fas ligand-induced death signals, 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, whereas the long form, FLIP(L), contains in addition a caspase-like domain in which the active-centre cysteine residue is substituted by a tyrosine residue. FLIPs and FLIP(L) interact with the adaptor protein FADD and the protease FLICE, and potently inhibit apoptosis induced by all known human death receptors. FLIP(L) 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 FLIP(L) 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.
广泛表达的蛋白Fas是肿瘤坏死因子受体家族的成员，可触发细胞凋亡。然而，Fas在细胞表面的表达并不一定使细胞易于受到Fas配体诱导的死亡信号的影响，这表明凋亡信号通路的抑制剂必定存在。在此我们报告一种凋亡抑制剂的特性，命名为FLIP（FLICE抑制蛋白），它主要在肌肉和淋巴组织中表达。短形式的FLIPs含有两个死亡效应结构域，在结构上与病毒凋亡FLIP抑制剂相关，而长形式的FLIP(L)还含有一个半胱天冬酶样结构域，其中活性中心的半胱氨酸残基被酪氨酸残基取代。FLIPs和FLIP(L)与衔接蛋白FADD和蛋白酶FLICE相互作用，并有效抑制所有已知人类死亡受体诱导的细胞凋亡。FLIP(L)在T细胞活化的早期阶段表达，但当T细胞易于受到Fas配体介导的细胞凋亡影响时消失。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FLIP(L)蛋白。因此，FLIP可能作为凋亡的重要调节因子参与组织稳态。
