Histone H2AX The missing link in AIF-mediated caspase-independent programmed necrosis
Histone H2AX The missing link in AIF-mediated caspase-independent programmed necrosis
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DOI：
10.4161/cc.9.16.12552
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发表时间：
2010-08-15
期刊：
影响因子：
4.3
通讯作者：
Susin, Santos A.
中科院分区：
文献类型：
--
作者：
Baritaud, Mathieu;Boujrad, Hanan;Susin, Santos A.
Caspase非依赖性程序性坏死是一种高度调控的细胞死亡，表现出形态和生化上的坏死特征，如较早的质膜通透性和乳酸脱氢酶(LDH)泄漏。这种形式的程序性细胞死亡(PCD)由AIF调控，AIF是一种依赖于FAD的氧化还原酶，从线粒体释放到细胞核，在那里它诱导染色质凝聚和DNA片段化。早在几年前，人们就发现，多聚腺苷二磷酸核糖聚合酶-1(PARP-1)、钙蛋白酶和Bax的顺序激活调节了线粒体AIF的释放，与程序性坏死相关。但是，当AIF在原子核中时会发生什么呢？这种蛋白质是如何引起染色质溶解和程序性坏死的？最近，我们已经解开了AIF在这种caspase非依赖性细胞死亡中的核作用的一些机制。事实上，AIF通过与H_2AX和亲环素A(CypA)形成DNA降解复合体的能力，在程序性坏死中发挥关键作用。AIF/H2AX连接确实是一个关键事件，并解释了核AIF的促凋亡作用。在这篇文章中，我们概述了细胞程序性死亡的现有知识，并讨论了AIF/H_2AX/CypA DNA降解复合体在调节这种原始形式的细胞死亡中的相关性。
Caspase-independent programmed necrosis is a highly regulated cellular demise that displays morphological and biochemical necrotic hallmarks, such as an earlier permeability of the plasma membrane and lactate dehydrogenase (LDH) leakiness. This form of programmed cell death (PCD) is regulated by AIF, a FAD-dependent oxidoreductase, which is released from the mitochondria to the nucleus where it induces chromatin tcondensation and DNA fragmentation. Some years ago, it was established that the sequential activation of poly(ADP-ribose) polymerase-1 (PARP-1), calpains and Bax regulates the mitochondrial AIF release associated to programmed necrosis. But, what happens when AIF is in the nucleus? How does this protein induce chromatinolysis and programmed necrosis? Recently, we have unraveled some of the mechanisms underlying the nuclear action of AIF in this type of caspase-independent cell death. Indeed, AIF plays a key role in programmed necrosis by its ability to organize a DNA-degrading complex with H2AX and Cyclophiline A (CypA). The AIF/H2AX link is indeed a critical event and explains the nuclear AIF apoptogenic action. In the present article, we outline the current knowledge on cell death by programmed necrosis and discuss the relevance of the AIF/H2AX/CypA DNA-degrading complex in the regulation of this original form of cell death.