Dimethyl fumarate dampens IL-17-ACT1-TBK1 axis-mediated phosphorylation of Regnase-1 and suppresses IL-17-induced IκB-ζ expression
Dimethyl fumarate dampens IL-17-ACT1-TBK1 axis-mediated phosphorylation of Regnase-1 and suppresses IL-17-induced IκB-ζ expression
复制标题
富马酸二甲酯抑制 IL-17-ACT1-TBK1 轴介导的 Regnase-1 磷酸化并抑制 IL-17 诱导的 IκB-ζ 表达
DOI：
10.1016/j.bbrc.2019.11.036
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发表时间：
2020
影响因子：
3.1
通讯作者：
Matsuda Tadashi
中科院分区：
文献类型：
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作者：
Ohgakiuchi Yui;Saino Yuka;Muromoto Ryuta;Komori Yuki;Sato Ami;Hirashima Koki;Kitai Yuichi;Kashiwakura Jun-ichi;Oritani Kenji;Matsuda Tadashi
由细胞因子白细胞介素-17 A（IL-17）引起的信号传导对于抗菌防御反应是重要的，而过量的IL-17产生导致自身免疫性疾病，如牛皮癣和多发性硬化症。IL-17诱导的mRNA稳定已被认为是IL-17信号传导的独特且重要的特征。以前，我们证明了IL-17信号蛋白ACT 1是抵抗核糖核酸酶Regnase-1引起的核因子κ B zeta（IκB-zeta）mRNA降解的组成型抑制剂所必需的。然而，关于IL-17刺激的细胞中mRNA稳定化机制的信息仍然不足。在本研究中，我们的目的是更详细地阐明机制，并确定一种药物，可以抑制IL-17诱导的mRNA稳定。使用小干扰RNA和TANK结合激酶1（TBK 1）抑制剂的实验表明，TBK 1是通过Regnase-1磷酸化稳定IκB-β mRNA所必需的。有趣的是，这种TBK 1介导的Regnase-1磷酸化通过添加富马酸二甲酯（DMF）来抑制，DMF是一种亲电子小分子，已用于治疗IL-17相关的自身免疫性疾病。ACT 1细胞定位的共聚焦显微镜观察显示，DMF处理导致ACT 1核点的消失和ACT 1的核周积聚。这些结果表明，DMF是一种小分子，可损害IL-17诱导的ACT 1-TBK 1通路活化，从而抑制IL-17诱导的mRNA稳定。
The signaling elicited by the cytokine interleukin-17A (IL-17) is important for antimicrobial defense responses, whereas excessive IL-17 production leads to autoimmune diseases such as psoriasis and multiple sclerosis. IL-17–induced stabilization of mRNAs has been recognized as a unique and important feature of IL-17 signaling. Previously, we demonstrated that IL-17 signaling protein ACT1 is required to counteract constitutive inhibitor of nuclear factor kappa B zeta (IκB-ζ) mRNA degradation by the ribonuclease Regnase-1. However, information about the mechanism of mRNA stabilization in IL-17–stimulated cells remains insufficient. In the present study, we aimed to clarify the mechanism in more detail and identify an agent that can inhibit IL-17–induced mRNA stabilization. Experiments using small interfering RNA and an inhibitor of TANK-binding kinase 1 (TBK1) revealed that TBK1 was required for IκB-ζ mRNA stabilization through Regnase-1 phosphorylation. Intriguingly, this TBK1-mediated phosphorylation of Regnase-1 was suppressed by the addition of dimethyl fumarate (DMF), an electrophilic small molecule that has been used to treat IL-17–related autoimmune diseases. Confocal microscopic observation of the cellular localization of ACT1 revealed that DMF treatment resulted in the disappearance of ACT1 nuclear dots and perinuclear accumulation of ACT1. These results suggested that DMF is a small molecule that compromises IL-17–induced activation of the ACT1-TBK1 pathway, thereby inhibiting IL-17–induced mRNA stabilization.