Stimulus-Dependent Inhibitor of Apoptosis Protein Expression Prolongs the Duration of B Cell Signalling.
Stimulus-Dependent Inhibitor of Apoptosis Protein Expression Prolongs the Duration of B Cell Signalling.
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DOI：
10.1038/srep27706
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发表时间：
2016-06-09
影响因子：
4.6
通讯作者：
Okada-Hatakeyama M
中科院分区：
文献类型：
--
作者：
Shinohara H;Inoue K;Yumoto N;Nagashima T;Okada-Hatakeyama M
信号活动的不同动态行为可以在不同的细胞中诱导不同的生物反应。然而，决定免疫细胞中激酶活性动力学的分子机制尚不清楚。在这项研究中，我们发现B细胞中B细胞受体(BCR)-和cd40信号通路中i - κB激酶（IKK）和细胞外信号调节激酶（ERK）活性的持续时间受到转录反馈回路的调节。我们在BCR或CD40刺激后进行了时间过程转录组分析，并确定了以下四个候选基因作为IKK和ERK的反馈调节因子：凋亡抑制蛋白（IAP）、TNF α诱导蛋白3、双特异性磷酸酶5和芽生同源物2。定量实验和数学模型表明，IAP抑制缩短了BCR和CD40通路刺激后IKK和ERK活性的持续时间，表明IAP在B细胞信号传导中的积极作用。此外，IAP阻断诱导的瞬时激酶活性降低了延迟表达基因的水平。总之，我们的研究结果表明，IKK和ERK的活性持续时间可以通过正、负转录反馈的协调调节来微调，这些网络特性决定了B细胞的生物学输出。
Different dynamic behaviours of signalling activity can induce distinct biological responses in a variety of cells. However, the molecular mechanisms that determine the dynamics of kinase activities in immune cells are not well understood. In this study, we showed that the duration of both IκB kinase (IKK) and extracellular signal-regulated kinase (ERK) activities in B cell receptor (BCR)- and CD40-signalling pathways in B cells were regulated by transcriptional feedback loops. We conducted a time-course transcriptome analysis after BCR or CD40 stimulation and identified the following four candidate genes as feedback regulators for IKK and ERK: inhibitor of apoptosis protein (IAP), TNF alpha-induced protein 3, dual-specificity phosphatase 5, and sprouty homolog 2. Quantitative experiments and mathematical modelling suggested that IAP inhibition shortened the duration of IKK and ERK activity following both BCR and CD40 pathway stimulation, indicating a positive role for IAP in B cell signalling. Furthermore, transient kinase activities induced by IAP blockage reduced the levels of delayed expression genes. Together, our findings suggest that IKK and ERK activity durations can be fine-tuned by the coordinated regulation of positive and negative transcriptional feedback and that these network properties determine the biological output of B cells.