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首页> 外文期刊>Molecular and Cellular Biology >Thioredoxin and TRAF Family Proteins Regulate Reactive Oxygen Species-Dependent Activation of ASK1 through Reciprocal Modulation of the N-Terminal Homophilic Interaction of ASK1
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Thioredoxin and TRAF Family Proteins Regulate Reactive Oxygen Species-Dependent Activation of ASK1 through Reciprocal Modulation of the N-Terminal Homophilic Interaction of ASK1

机译：硫氧还蛋白和TRAF家族蛋白通过相互调节ASK1的N终端嗜好相互作用来调节活性氧依赖于ASK1的激活。

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Apoptosis signal-regulating kinase 1 (ASK1), a member of the mitogen-activated protein kinase kinase kinase family, plays pivotal roles in reactive oxygen species (ROS)-induced cellular responses. In resting cells, endogenous ASK1 constitutively forms a homo-oligomerized but still inactive high-molecular-mass complex including thioredoxin (Trx), which we designated the ASK1 signalosome. Upon ROS stimulation, the ASK1 signalosome unbinds from Trx and forms a fully activated higher-molecular-mass complex, in part by recruitment of tumor necrosis factor receptor-associated factor 2 (TRAF2) and TRAF6. However, the precise mechanisms by which Trx inhibits and TRAF2 and TRAF6 activate ASK1 have not been elucidated fully. Here we demonstrate that the N-terminal homophilic interaction of ASK1 through the N-terminal coiled-coil domain is required for ROS-dependent activation of ASK1. Trx inhibited this interaction of ASK1, which was, however, enhanced by expression of TRAF2 or TRAF6 or by treatment of cells with H2O2. Furthermore, the H2O2-induced interaction was reduced by double knockdown of TRAF2 and TRAF6. These findings demonstrate that Trx, TRAF2, and TRAF6 regulate ASK1 activity by modulating N-terminal homophilic interaction of ASK1.
机译：凋亡信号调节激酶1（ASK1），丝裂原激活的蛋白激酶激酶激酶家族的成员，在活性氧（ROS）诱导的细胞反应中起关键作用。在静止细胞中，内源性ASK1组成性地形成了一种均聚的，但仍无活性的高分子质量复合物，包括硫氧还蛋白（Trx），我们将其称为ASK1信号体。在ROS刺激后，ASK1信号小体从Trx脱离并形成完全活化的高分子质量复合物，部分是通过募集肿瘤坏死因子受体相关因子2（TRAF2）和TRAF6来实现的。但是，尚未完全阐明Trx抑制TRAF2和TRAF6激活ASK1的确切机制。在这里，我们证明了ASK1的N末端同质相互作用通过N末端卷曲螺旋结构域是ROS依赖的ASK1活化所必需的。 Trx抑制了ASK1的这种相互作用，但是，通过表达TRAF2或TRAF6或用H 2 O 2 处理细胞可以增强ASK1的这种相互作用。此外，TRAF2和TRAF6的双重敲低减少了H 2 O 2 诱导的相互作用。这些发现表明，Trx，TRAF2和TRAF6通过调节ASK1的N端同源相互作用来调节ASK1活性。

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