14-3-3∈ and 14-3-3σ Inhibit Toll-like Receptor (TLR)-mediated Proinflammatory Cytokine Induction (Retracted Article)
14-3-3∈ and 14-3-3σ Inhibit Toll-like Receptor (TLR)-mediated Proinflammatory Cytokine Induction (Retracted Article)
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DOI：
10.1074/jbc.m112.367490
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发表时间：
2012-11-09
影响因子：
4.8
通讯作者：
Miggin, Sinead M.
中科院分区：
文献类型：
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作者：
Butt, Aisha Qasim;Ahmed, Suaad;Miggin, Sinead M.
Toll 样受体 (TLR) 是一组模式识别受体，在诱导针对细菌和病毒感染的先天免疫反应中发挥着至关重要的作用。 TLR3 已成为病毒双链 RNA 的关键传感器。因此，更清楚地了解调节 TLR3 信号传导的生物过程至关重要。应用蛋白质组学来了解 TLR 信号传导动力学的研究有限。在此，蛋白质组学方法鉴定出 14-3-3 是 TLR 信号复合体的一个元件，14-3-3 σ 蛋白是 TLR 信号复合体的新成员。针对 14-3-3 和 14-3-3 sigma 在 TLR 信号传导中的功能特征，我们发现这两种蛋白都会损害 TLR2、TLR3、TLR4、TLR7/8 和 TLR9 配体诱导的 IL-6、TNF α 和 IFN-β 产生。我们还表明，14-3-3 是 14-3-3 σ 的一个元件，并且 14-3-3 σ 会损害 TLR2-、TLR3-、TLR4-、TLR7/8- 和 TLR9 介导的 NF-κ B 和 IFN-β 报告基因活性。有趣的是，虽然14-3-3蛋白抑制poly(I:C)介导的RANTES产生，但14-3-3蛋白以Mal(MyD88适配器样)/MyD88依赖性方式增强Pam(3)CSK(4)、LPS、R848和CpG介导的RANTES产生(调节正常T细胞表达和分泌的激活)。 14-3-3 是 的一个元件，并且 14-3-3 σ 也与 TLR 衔接子以及 TRAF3 和 TRAF6 结合。我们的研究最终表明，14-3-3 是 14-3-3 sigma 的一个元素，并且 14-3-3 sigma 通过调节 TLR 信号通路，在平衡宿主对病毒和细菌感染的炎症反应方面发挥着重要的调节作用。因此，14-3-3 蛋白的操作可能代表炎症和感染的新治疗靶点。
Toll-like receptors (TLRs) are a group of pattern recognition receptors that play a crucial role in the induction of the innate immune response against bacterial and viral infections. TLR3 has emerged as a key sensor of viral double-stranded RNA. Thus, a clearer understanding of the biological processes that modulate TLR3 signaling is essential. Limited studies have applied proteomics toward understanding the dynamics of TLR signaling. Herein, a proteomics approach identified 14-3-3 is an element of and 14-3-3 sigma proteins as new members of the TLR signaling complex. Toward the functional characterization of 14-3-3 is an element of and 14-3-3 sigma in TLR signaling, we have shown that both of these proteins impair TLR2, TLR3, TLR4, TLR7/8, and TLR9 ligand-induced IL-6, TNF alpha, and IFN-beta production. We also show that 14-3-3 is an element of and 14-3-3 sigma impair TLR2-, TLR3-, TLR4-, TLR7/8-, and TLR9-mediated NF-kappa B and IFN-beta reporter gene activity. Interestingly, although the 14-3-3 proteins inhibit poly(I: C)mediated RANTES production, 14-3-3 proteins augment Pam(3)CSK(4), LPS, R848, and CpG-mediated production of RANTES (regulated on activation normal T cell expressed and secreted) in a Mal (MyD88 adaptor-like)/MyD88-dependent manner. 14-3-3 is an element of and 14-3-3 sigma also bind to the TLR adaptors and to both TRAF3 and TRAF6. Our study conclusively shows that 14-3-3 is an element of and 14-3-3 sigma play a major regulatory role in balancing the host inflammatory response to viral and bacterial infections through modulation of the TLR signaling pathway. Thus, manipulation of 14-3-3 proteins may represent novel therapeutic targets for inflammatory conditions and infections.