Molecular evidence for the nuclear localization of FADD
Molecular evidence for the nuclear localization of FADD
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DOI：
10.1038/sj.cdd.4401237
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发表时间：
2003-07-01
影响因子：
12.4
通讯作者：
Cidlowski, JA
中科院分区：
文献类型：
--
作者：
Gómez-Angelats, M;Cidlowski, JA
Fas相关死亡结构域(FADD)适配器蛋白FADD/Mort-1是肿瘤坏死因子受体(TNFR)超家族成员在细胞死亡过程中通过死亡受体激活而招募的。由于大多数研究都集中在FADD与质膜蛋白的相互作用上，FADD的亚细胞定位被认为局限于细胞质。在这份报告中，我们首次证明了FADD同时存在于细胞质和细胞核中，其核定位依赖于位于蛋白质死亡效应区域(DED)的强核定位和核输出信号(分别为NLS和NES)。具体地说，我们发现人类蛋白的一个保守的碱性KRK35序列对于FADD的核定位是必要的，因为这个基序的破坏导致FADD被限制在细胞质中。此外，我们还证明了DED中富含亮氨酸的LTELKFLCL28基序是FADD核出口所必需的。在功能上，FADD的NES突变及其在核中的封闭降低了FADD在FADD缺陷的T细胞中重组的细胞死亡诱导效果。
The Fas-associated death domain (FADD) adaptor protein FADD/Mort-1 is recruited by several members of the tumor necrosis factor receptor (TNFR) superfamily during cell death activated via death receptors. Since most studies have focused on the interaction of FADD with plasma membrane proteins, FADD's subcellular location is thought to be confined to the cytoplasm. In this report, we show for the first time that FADD is present in both the cytoplasm and the nucleus of cells, and that its nuclear localization relies on strong nuclear localization and nuclear export signals (NLS and NES, respectively) that reside in the death-effector domain (DED) of the protein. Specifically, we found that a conserved basic KRK35 sequence of the human protein is necessary for FADD's nuclear localization, since disruption of this motif leads to the confinement of FADD in the cytoplasm. Furthermore, we show that the leucine-rich motif LTELKFLCL28 in the DED is necessary for FADD's nuclear export. Functionally, mutation of the NES of FADD and its seclusion in the nucleus reduces the cell death-inducing efficacy of FADD reconstituted in FADD-deficient T cells.