凋亡诱导因子是线粒体内介导核凋亡的最主要蛋白质之一

AIF is One of the Critical Mitochondrial Proteins to Mediate Nuclear Apoptosis

凋亡诱导因子 (apoptosis inducingfactor ,AIF)基因定位于X染色体上 ,其编码产物是一种可直接介导细胞核凋亡的效应分子 .鼠AIF前体蛋白在胞浆中合成后 ,通过其N端的线粒体定位信号 (MLS)有效地穿入线粒体膜间隙 ,然后在 10 2位甘氨酸处水解掉MLS ,其余部分再与黄素腺嘌呤二核苷酸 (FAD)结合 ,并重新折叠成为具有促凋亡潜能的成熟AIF分子 ,分子质量为 5 7ku .当凋亡信号刺激时 ,AIF分子从线粒体释放到胞浆 ,然后转位到细胞核内 ,引起染色体核周边凝集和DNA呈大片段断裂 (～ 5 0kb) .该作用不受广谱caspases抑制剂z VAD .fmk的抑制 ,也不受Bcl 2过量表达的影响 .基因剔除实验表明 ,AIF蛋白的促凋亡活性是胚胎小鼠形态发生过程中类胚体成腔所必需的 ,而且是AIF独立作用的结果 ,可以不依赖caspase 3的活性 .因此AIF介导的细胞凋亡可能代表了独立于caspase通路之外的另一条更原始、更保守的凋亡途径 .

Apoptosis-inducing factor (AIF), whose gene lies in X-chromosome, is likely an apoptogenic effector protein to mediates nuclear apoptosis directly. Once synthesized in the cytoplasm, the mouse AIF-precursor preprotein can be effectively imported into the mitochondrial intermembrane space through its N-terminal mitochondrial localization sequence (MLS). Then the MLS is cut off at position Gly 102 of the full-length preprotein, and the remains is refolded and bound with FAD group to produce the apoptogenic mature AIF, with a relative molecular mass of 57 ku. When death stimuli present, AIF is released from mitochondria to the cytoplasm and then to the nucleus, inducing peripheral chromatin condensation and large-scale fragmentation of DNA (similar to50 kb). These effects cannot be prevented either by the presence of wide-spectrum caspase inhibitor z-VAD.fmk or by the overexpression of Bcl-2. The evidences of gene knockout experiments indicate that AIF is essential for the cavitation of embryoid bodies during mouse morphogenesis, and the cavitation can be caused by AIF itself, independent on caspase-3 activity. Therefore, AIF-mediated cell death maybe constitutes a caspases-independent, more ancient and conserved apoptosis pathway.