IL-17 通过 RNA 结合蛋白 Arid5a 整合多个自我强化、前馈机制。
IL-17 integrates multiple self-reinforcing, feed-forward mechanisms through the RNA binding protein Arid5a.
机构信息
Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA.
出版信息
Sci Signal. 2018 Oct 9;11(551):eaat4617. doi: 10.1126/scisignal.aat4617.
Interleukin-17A (IL-17A) not only stimulates immunity to fungal pathogens but also contributes to autoimmune pathology. IL-17 is only a modest activator of transcription in experimental tissue culture settings. However, IL-17 controls posttranscriptional events that enhance the expression of target mRNAs. Here, we showed that the RNA binding protein (RBP) Arid5a (AT-rich interactive domain-containing protein 5a) integrated multiple IL-17-driven signaling pathways through posttranscriptional control of mRNA. IL-17 induced expression of Arid5a, which was recruited to the adaptor TRAF2. Arid5a stabilized IL-17-induced cytokine transcripts by binding to their 3' untranslated regions and also counteracted mRNA degradation mediated by the endoribonuclease MCPIP1 (Regnase-1). Arid5a inducibly associated with the eukaryotic translation initiation complex and facilitated the translation of the transcription factors (TFs) IκBζ ( ) and C/EBPβ (). These TFs in turn transactivated IL-17-dependent promoters. Together, these data indicated that Arid5a orchestrates a feed-forward amplification loop, which promoted IL-17 signaling by controlling mRNA stability and translation.
白细胞介素-17A(IL-17A)不仅刺激对真菌病原体的免疫,而且还有助于自身免疫病理学。在实验组织培养环境中,IL-17 只是转录的适度激活剂。然而,IL-17 控制着增强靶 mRNA 表达的转录后事件。在这里,我们表明 RNA 结合蛋白(RBP)Arid5a(富含 AT 相互作用结构域蛋白 5a)通过对 mRNA 的转录后控制,整合了多个由 IL-17 驱动的信号通路。IL-17 诱导 Arid5a 的表达,Arid5a 被募集到衔接 TRAF2。Arid5a 通过结合其 3'非翻译区稳定由内切核酸酶 MCPIP1(Regnase-1)介导的 IL-17 诱导的细胞因子转录本的降解。Arid5a 可诱导地与真核翻译起始复合物结合,并促进转录因子(TFs)IκBζ()和 C/EBPβ()的翻译。这些 TF 反过来又反式激活了依赖于 IL-17 的启动子。总之,这些数据表明 Arid5a 协调了一个正反馈放大环,通过控制 mRNA 稳定性和翻译来促进 IL-17 信号。