Export of mitochondrial AIF in response to proapoptotic stimuli depends on processing at the intermembrane space
Export of mitochondrial AIF in response to proapoptotic stimuli depends on processing at the intermembrane space
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DOI：
10.1038/sj.emboj.7600614
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发表时间：
2005-04-06
期刊：
影响因子：
11.4
通讯作者：
Mihara, K
中科院分区：
文献类型：
--
作者：
Otera, H;Ohsakaya, S;Mihara, K
凋亡诱导因子（AIF）是一种线粒体膜间黄素蛋白，在促凋亡刺激下易位到细胞核，诱导细胞核凋亡。在这里，我们发现AIF是作为一个类似67-kDa的前蛋白合成的，带有一个n端延伸，并导入线粒体，在那里它被加工成类似62-kDa的成熟形式。拓扑分析表明，成熟的AIF是一种i型内膜蛋白，其n端暴露于基质，c端暴露于膜间隙。诱导凋亡后，成熟的AIF在膜间空间发生caspase独立加工成类似57-kDa的形式，并将加工后的形式释放到细胞质中。Bcl-2或Bcl-XL抑制这两种事件。这些发现表明，线粒体中AIF的释放发生两步过程：在膜间空间通过凋亡诱导的加工从内膜脱离，并转运到细胞质中。结果还表明，在caspase不依赖的细胞死亡中，存在一种独特的蛋白酶，受促凋亡刺激调节。
Apoptosis-inducing factor (AIF) is a mitochondrial intermembrane flavoprotein that is translocated to the nucleus in response to proapoptotic stimuli, where it induces nuclear apoptosis. Here we show that AIF is synthesized as an similar to 67-kDa preprotein with an N-terminal extension and imported into mitochondria, where it is processed to the similar to 62-kDa mature form. Topology analysis revealed that mature AIF is a type-I inner membrane protein with the N-terminus exposed to the matrix and the C-terminal portion to the intermembrane space. Upon induction of apoptosis, processing of mature AIF to an similar to 57-kDa form occurred caspase-independently in the intermembrane space, releasing the processed form into the cytoplasm. Bcl-2 or Bcl-XL inhibited both these events. These findings indicate that AIF release from mitochondria occurs by a two-step process: detachment from the inner membrane by apoptosis-induced processing in the intermembrane space and translocation into the cytoplasm. The results also suggest the presence of a unique protease that is regulated by proapoptotic stimuli in caspase-independent cell death.