The carboxy terminal c-tail of BNip3 is crucial in induction of mitochondrial permeability transition in isolated mitochondrial
The carboxy terminal c-tail of BNip3 is crucial in induction of mitochondrial permeability transition in isolated mitochondrial
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DOI：
10.1006/abbi.2001.2673
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发表时间：
2002-02-15
影响因子：
3.9
通讯作者：
Park, JH
中科院分区：
文献类型：
--
作者：
Kim, JY;Cho, JJ;Park, JH
BNip3是Bcl2家族蛋白中的一员，具有促凋亡活性。它含有Bcl2同源物(1311)3和单羧基末端膜锚定结构域(TM)，它针对特定的细胞内细胞器，特别是线粒体。线粒体通过称为通透性转换孔(PTP)的大电导通道释放致细胞凋亡的因子，在细胞凋亡中发挥重要作用。尽管BNip3在高表达时与线粒体结合，但包括线粒体级联和功能结构域在内的凋亡途径仍不清楚。在这篇报道中，我们证明了重组BNip3(RBNip3)可诱导线粒体通透性转换(MPT)和细胞色素c的释放，这一作用可被PT抑制剂环孢素A(CsA)抑制。在突变分析的基础上，我们进一步证明BNip3的羧基末端是诱导PT和细胞色素c释放所必需的，而不是BH3。此外，在没有诱导PT和细胞色素c释放的TM替换突变体中加入羧基末端c-ail，恢复了PT的诱导活性。综上所述，我们的结果表明，BNip3通过PT诱导发挥促凋亡活性，而羧基末端c-ail对此起关键作用。(C)2002年埃尔塞维尔科学公司(美国)。
BNip3 is a member of Bcl-2 family proteins that displays proapoptotic activity. It contains Bcl-2 homology (1311) 3 and single carboxy terminal membrane-anchoring domain (TM), which targets to specific intracellular organelles, especially to mitochondria. Mitochondria play significant roles in apoptosis by releasing apopto-genic factors through large conductance channel known as permeability transition pore (PTP). Although BNip3 associates with mitochondria when overexpressed, apoptotic pathways including mitochondrial cascade and functional domains of BNip3 are still unknown. in this report, we demonstrate that recombinant BNip3 (rBNip3) induces mitochondrial permeability transition (MPT) and cytochrome c release from isolated mitochondria, which are inhibited by the PT inhibitor cyclosporin A (CsA). We further show that carboxy terminal tail of BNip3, but not BH3, is essential for the induction of PT and cytochrome c release on the base of mutational analysis. Moreover, addition of carboxy terminal c-tail to TM substitution mutant, which did not induce the PT and cytochrome c release, restored PT-inducing activity. Taken together, our results suggest that BNip3 exerts proapoptotic activity through PT induction and that carboxy terminal c-tail is crucial for it. (C) 2002 Elsevier Science (USA).