harakiri, a novel regulator of cell death, encodes a protein that activates apoptosis and interacts selectively with survival-promoting proteins Bcl-2 and Bcl-X-L
harakiri, a novel regulator of cell death, encodes a protein that activates apoptosis and interacts selectively with survival-promoting proteins Bcl-2 and Bcl-X-L
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DOI：
10.1093/emboj/16.7.1686
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发表时间：
1997-04-01
期刊：
影响因子：
11.4
通讯作者：
Nunez, G
中科院分区：
文献类型：
--
作者：
Inohara, N;Ding, LY;Nunez, G
程序性细胞死亡对于器官发育和组织稳态至关重要，其失调与小鼠和人类多种疾病的发生有关。控制细胞死亡的精确机制尚未完全阐明，但众所周知，这种形式的细胞死亡是由垂死细胞中激活的遗传程序调节的。在这里，我们报告了 harakiri（一种调节细胞凋亡的新基因）的鉴定、克隆和表征。 harakiri 的产物 Hrk 与死亡阻遏蛋白 Bcl-2 和 Bcl-X-L 发生物理相互作用，但不与促死亡同源物 Bax Bax Bak 发生相互作用，Hrk 缺乏保守的 BH1 和 BH2 区域，且与 Bcl-2 家族成员或任何其他蛋白质具有显着同源性，但与 BH3 区域表现出高度同源性的八个氨基酸除外。 Hrk 的表达会诱导细胞死亡，而细胞死亡可被 Bcl-2 和 Bcl-X-L 抑制。包括保守的 BH3 区域在内的 16 个氨基酸的缺失消除了 Hrk 与哺乳动物细胞中的 Bcl-2 和 Bcl-X-L 相互作用的能力。此外，这种 Hrk 突变形式 (Hrk Delta BH3) 的杀伤活性被消除或显着降低，表明 Hrk 至少部分通过与 Bcl-2 和 Bcl-X-L 提供的相互作用并抑制其提供的保护来激活细胞死亡。由于 Hrk 缺乏定义 Bcl-2 家族成员的保守 BH1 和 BH2 残基，因此我们提出 Hrk 和 Bik/Nbk（另一种激活细胞凋亡的含 BH3 蛋白）代表了一类新的蛋白，它们通过选择性地与促进存活的 Bcl-2 和 Bcl-X-L 相互作用来调节细胞凋亡。
Programmed cell death is essential in organ development and tissue homeostasis and its deregulation is associated with the development of several diseases in mice and humans. The precise mechanisms that control cell death have not been elucidated fully, but it is well established that this form of cellular demise is regulated by a genetic program which is activated in the dying cell. Here we report the identification, cloning and characterization of harakiri, a novel gene that regulates apoptosis. The product of harakiri, Hrk, physically interacts with the death-repressor proteins Bcl-2 and Bcl-X-L, but not with death-promoting homologs, Bax Bax Bak, Hrk lacks conserved BH1 and BH2 regions and significant homology to Bcl-2 family members or any other protein, except for a stretch of eight amino acids that exhibits high homology with BH3 regions. Expression of Hrk induces cell death which is inhibited by Bcl-2 and Bcl-X-L. Deletion of 16 amino acids including the conserved BH3 region abolished the ability of Hrk to interact with Bcl-2 and Bcl-X-L in mammalian cells. Moreover, the killing activity of this mutant form of Hrk (Hrk Delta BH3) was eliminated or dramatically reduced, suggesting that Hrk activates cell death at least in part by interacting with and inhibiting the protection afforded by Bcl-2 and Bcl-X-L. Because Hrk lacks conserved BH1 and BH2 remains that define Bcl-2 family members, we propose that Hrk and Bik/Nbk, another BH3-containing protein that activates apoptosis, represent a novel class of proteins that regulate apoptosis by interacting selectively with survival-promoting Bcl-2 and Bcl-X-L.