Cyclophilin A participates in the nuclear translocation of apoptosis-inducing factor in neurons after cerebral hypoxia-ischemia.
Cyclophilin A participates in the nuclear translocation of apoptosis-inducing factor in neurons after cerebral hypoxia-ischemia.
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DOI：
10.1084/jem.20070193
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发表时间：
2007-08-06
期刊：
影响因子：
--
通讯作者：
Blomgren K
中科院分区：
文献类型：
--
作者：
Zhu C;Wang X;Deinum J;Huang Z;Gao J;Modjtahedi N;Neagu MR;Nilsson M;Eriksson PS;Hagberg H;Luban J;Kroemer G;Blomgren K
在脑缺氧缺血(HI)时，凋亡诱导因子(AIF)可以从线粒体移动到细胞核，参与染色质分解，并有助于细胞死亡的执行。以前的工作(Cande，C.，N.Vahsen，I.Kouranti，E.Schmitt，E.Daugas，C.Spahr，J.Luban，R.T.Kroemer，F.Giordanetto，C.Garrido，等)。2004年。癌基因。23：1514-1521)体外实验表明，AIF必须与亲环素A(CypA)相互作用，形成促凋亡的DNA降解复合体。我们解决了消除CypA是否可以提供体内神经保护的问题。9d龄野生型(WT)、CypA+/−或CypA−/−小鼠造成单侧脑缺血。与WT小鼠相比，CypA−/−小鼠HI后的脑梗塞体积缩小了47%(P=0.0089)。重要的是，CypA−/−神经元没有表现出在WT神经元中观察到的HI诱导的AIF核移位。相反，在HI后，CypA在受损神经元的细胞核内积聚，在AIF缺陷的小丑小鼠中，CypA的这种核转位被抑制。AIF免疫共沉淀显示CypA共沉淀，但仅在损伤的缺血组织中表达。表面等离子体波谱显示重组AIF与CypA之间存在直接的分子相互作用。这些数据表明，AIF的致命性移位到细胞核需要与CypA相互作用，这表明了一种模型，在该模型中，通常位于不同细胞质中的两种蛋白质在一起移动到细胞核时获得了新的性质。
Upon cerebral hypoxia-ischemia (HI), apoptosis-inducing factor (AIF) can move from mitochondria to nuclei, participate in chromatinolysis, and contribute to the execution of cell death. Previous work (Cande, C., N. Vahsen, I. Kouranti, E. Schmitt, E. Daugas, C. Spahr, J. Luban, R.T. Kroemer, F. Giordanetto, C. Garrido, et al. 2004. Oncogene. 23:1514–1521) performed in vitro suggests that AIF must interact with cyclophilin A (CypA) to form a proapoptotic DNA degradation complex. We addressed the question as to whether elimination of CypA may afford neuroprotection in vivo. 9-d-old wild-type (WT), CypA+/−, or CypA−/− mice were subjected to unilateral cerebral HI. The infarct volume after HI was reduced by 47% (P = 0.0089) in CypA−/− mice compared with their WT littermates. Importantly, CypA−/− neurons failed to manifest the HI-induced nuclear translocation of AIF that was observed in WT neurons. Conversely, CypA accumulated within the nuclei of damaged neurons after HI, and this nuclear translocation of CypA was suppressed in AIF-deficient harlequin mice. Immunoprecipitation of AIF revealed coprecipitation of CypA, but only in injured, ischemic tissue. Surface plasmon resonance revealed direct molecular interactions between recombinant AIF and CypA. These data indicate that the lethal translocation of AIF to the nucleus requires interaction with CypA, suggesting a model in which two proteins that normally reside in separate cytoplasmic compartments acquire novel properties when moving together to the nucleus.
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影响因子：
64.5
作者：
LIU, J;FARMER, JD;SCHREIBER, SL
通讯作者：
SCHREIBER, SL
影响因子：
4.4
作者：
Colgan, J;Asmal, M;Luban, J
通讯作者：
Luban, J
DOI：
10.1038/nsb836
发表时间：
2002-09-01
期刊：
NATURE STRUCTURAL BIOLOGY
影响因子：
--
作者：
Ye, H;Cande, C;Wu, H
通讯作者：
Wu, H
影响因子：
4.7
作者：
Zhu, CL;Xu, FL;Hagberg, H
通讯作者：
Hagberg, H
影响因子：
4.7
作者：
Zhu, CL;Qiu, L;Blomgren, K
通讯作者：
Blomgren, K