Kataoka T, Holler N, Micheau O, Martinon F, Tinel A, Hofmann K, Tschopp J
Institute of Biochemistry, University of Lausanne, Chemin des Boveresses 155, CH-1066 Epalinges, Switzerland.
J Biol Chem. 2001 Jun 1;276(22):19548-54. doi: 10.1074/jbc.M010520200. Epub 2001 Mar 21.
The Bcl-2 family of proteins plays a central regulatory role in apoptosis. We have identified a novel, widely expressed Bcl-2 member which we have named Bcl-rambo. Bcl-rambo shows overall structural homology to the anti-apoptotic Bcl-2 members containing conserved Bcl-2 homology (BH) motifs 1, 2, 3, and 4. Unlike Bcl-2, however, the C-terminal membrane anchor region is preceded by a unique 250 amino acid insertion containing two tandem repeats. No interaction of Bcl-rambo with either anti-apoptotic (Bcl-2, Bcl-x(L), Bcl-w, A1, MCL-1, E1B-19K, and BHRF1) or pro-apoptotic (Bax, Bak, Bik, Bid, Bim, and Bad) members of the Bcl-2 family was observed. In mammalian cells, Bcl-rambo was localized to mitochondria, and its overexpression induces apoptosis that is specifically blocked by the caspase inhibitors, IAPs, whereas inhibitors controlling upstream events of either the 'death receptor' (FLIP, FADD-DN) or the 'mitochondrial' pro-apoptotic pathway (Bcl-x(L)) had no effect. Surprisingly, the Bcl-rambo cell death activity was induced by its membrane-anchored C-terminal domain and not by the Bcl-2 homology region. Thus, Bcl-rambo constitutes a novel type of pro-apoptotic Bcl-2 member that triggers cell death independently of its BH motifs.
Bcl-2蛋白家族在细胞凋亡过程中发挥着核心调控作用。我们鉴定出一种新的、广泛表达的Bcl-2成员，将其命名为Bcl-rambo。Bcl-rambo与含有保守Bcl-2同源（BH）基序1、2、3和4的抗凋亡Bcl-2成员在整体结构上具有同源性。然而，与Bcl-2不同的是，其C末端膜锚定区域之前有一个独特的包含两个串联重复序列的250个氨基酸的插入序列。未观察到Bcl-rambo与Bcl-2家族的抗凋亡成员（Bcl-2、Bcl-x(L)、Bcl-w、A1、MCL-1、E1B-19K和BHRF1）或促凋亡成员（Bax、Bak、Bik、Bid、Bim和Bad）之间存在相互作用。在哺乳动物细胞中，Bcl-rambo定位于线粒体，其过表达诱导的细胞凋亡可被半胱天冬酶抑制剂IAPs特异性阻断，而控制“死亡受体”（FLIP、FADD-DN）或“线粒体”促凋亡途径（Bcl-x(L)）上游事件的抑制剂则无作用。令人惊讶的是，Bcl-rambo的细胞死亡活性是由其膜锚定的C末端结构域诱导的，而非Bcl-2同源区域。因此，Bcl-rambo构成了一种新型的促凋亡Bcl-2成员，其触发细胞死亡独立于其BH基序。
