Oxidative, multistep activation of the noncanonical NF-κB pathway via disulfide Bcl-3/p50 complex
Oxidative, multistep activation of the noncanonical NF-κB pathway via disulfide Bcl-3/p50 complex
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DOI：
10.1096/fj.07-104109
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发表时间：
2009-01-01
期刊：
影响因子：
4.8
通讯作者：
Diederich, Marc
中科院分区：
文献类型：
--
作者：
Cristofanon, Silvia;Morceau, Franck;Diederich, Marc
丁硫氨酸亚磺胺(BSO)是一种众所周知的谷胱甘肽合成的抑制剂，产生缓慢的谷胱甘肽(GSH)耗竭和氧化应激；一些“应答”细胞通过反式激活生存蛋白Bcl-2来避免BSO诱导的死亡。在这里，我们发现BSO通过一个多步骤的过程激活了一个非规范的、抑制性的、不依赖于NF-kappa B和p65的NF-kappa B通路，从而导致了Bc1-2的上调。BSO诱导的缓慢GSH耗竭允许两个与氧化还原相关的阶段分离，即早期的硫醇失衡和晚期的坦率氧化应激；每一阶段都有助于p50-p50同源二聚体的逐步激活。早期阶段，与大量的硫醇耗尽相吻合，产生一个胞浆制备性复合体，由p50及其相互作用的Bcl-3通过蛋白间二硫键连接组成。后期，与活性氧的产生相吻合，可能通过p38激活，负责核靶向复合体和反式激活bc l-2。Cristofanon，S.，Morceau，F.，Scovassi，A.I.，Dicato，M.，Ghibeli，L.，Diederich，M.氧化，通过二硫键Bcl3/p50复合体多步激活非规范的NF-kappa B途径。FASE B J.23，45-57(2009)
Buthionine sulfoximine ( BSO) is a well-known inhibitor of glutathione synthesis, producing slow glutathione ( GSH) depletion and oxidative stress; some "responder" cells avoid BSO-induced death by trans-activating the prosurvival protein Bcl-2. Here we show that BSO activates a noncanonical, inhibitory NF-kappa B- and p65-independent NF-kappa B pathway via a multistep process leading to the up-regulation of Bcl-2. The slow BSO-induced GSH depletion allows separation of two redox-related phases, namely, early thiol disequilibrium and late frank oxidative stress; each phase contributes to the progressive activation of a p50-p50 homodimer. The early phase, coinciding with substantial thiol depletion, produces a cytosolic preparative complex, consisting of p50 and its interactor Bcl-3 linked by interprotein disulfide bridges. The late phase, coinciding with reactive oxygen species production, is responsible, probably via p38 activation, for nuclear targeting of the complex and trans-activation of Bcl-2. Cristofanon, S., Morceau, F., Scovassi, A. I., Dicato, M., Ghibelli, L., Diederich, M. Oxidative, multistep activation of the noncanonical NF-kappa B pathway via disulfide Bcl-3/p50 complex. FASEB J. 23, 45-57 ( 2009)