Modulation of calcium-induced cell death in human neural stem cells by the novel peptidylarginine deiminase-AIF pathway.
Modulation of calcium-induced cell death in human neural stem cells by the novel peptidylarginine deiminase-AIF pathway.
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通过新型肽基精氨酸脱亚胺酶-AIF 途径调节钙诱导的人神经干细胞细胞死亡。
DOI：
10.1016/j.bbamcr.2014.02.018
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Ferretti,Patrizia
中科院分区：
文献类型：
--
作者：
U,KinPong;Subramanian,Venkataraman;Nicholas,AntonyP;Thompson,PaulR;Ferretti,Patrizia
pad（肽精氨酸脱亚胺酶）是一种钙依赖性酶，可以将蛋白质结合的精氨酸转化为瓜氨酸（瓜氨酸化/脱亚胺化），影响蛋白质的构象和功能。雏鸡脊髓损伤后PAD上调与广泛的组织损伤和再生能力丧失有关。在发现人类神经干细胞（hNSCs）表达PAD2和PAD3后，我们研究了PAD在这些细胞中的功能，并通过模拟钙诱导的继发性损伤反应来研究PAD3作为神经保护的潜在靶点。我们发现PAD3而不是PAD2是细胞生长/死亡的调节剂，并且PAD活性与caspase-3依赖性细胞死亡无关，但它是AIF（凋亡诱导因子）介导的细胞凋亡所必需的。PAD抑制阻止了PAD3与AIF的关联以及其转运到细胞核所需的AIF切割。最后，PAD抑制也阻碍钙诱导的细胞骨架分解和PAD3与波形蛋白的关联，我们发现这也与AIF有关；这表明，依赖于pad的细胞骨架解体可能在AIF转运到细胞核中起作用。这是第一个强调PAD活性在平衡hNSC存活/死亡中的作用的研究，确定了PAD3是钙诱导的细胞凋亡的重要上游调节剂，可以靶向减少神经损失，并揭示了相关机制。
PADs (peptidylarginine deiminases) are calcium-dependent enzymes that change protein-bound arginine to citrulline (citrullination/deimination) affecting protein conformation and function. PAD up-regulation following chick spinal cord injury has been linked to extensive tissue damage and loss of regenerative capability. Having found that human neural stem cells (hNSCs) expressed PAD2 and PAD3, we studied PAD function in these cells and investigated PAD3 as a potential target for neuroprotection by mimicking calcium-induced secondary injury responses. We show that PAD3, rather than PAD2 is a modulator of cell growth/death and that PAD activity is not associated with caspase-3-dependent cell death, but is required for AIF (apoptosis inducing factor)-mediated apoptosis. PAD inhibition prevents association of PAD3 with AIF and AIF cleavage required for its translocation to the nucleus. Finally, PAD inhibition also hinders calcium-induced cytoskeleton disassembly and association of PAD3 with vimentin, that we show to be associated also with AIF; together this suggests that PAD-dependent cytoskeleton disassembly may play a role in AIF translocation to the nucleus. This is the first study highlighting a role of PAD activity in balancing hNSC survival/death, identifying PAD3 as an important upstream regulator of calcium-induced apoptosis, which could be targeted to reduce neural loss, and shedding light on the mechanisms involved.