Science Signaling ( IF 6.7 ) Pub Date : 2018-10-09 , DOI: 10.1126/scisignal.aat4617 Nilesh Amatya 1 , Erin E Childs 1 , J Agustin Cruz 1 , Felix E Y Aggor 1 , Abhishek V Garg 1 , Andrea J Berman 2 , Johann E Gudjonsson 3 , Ulus Atasoy 4 , Sarah L Gaffen 1
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 (Nfkbiz ) and C/EBPβ (Cebpb). 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.
中文翻译:
IL-17 通过 RNA 结合蛋白 Arid5a 整合多种自我强化、前馈机制
白细胞介素 17A (IL-17A) 不仅能刺激对真菌病原体的免疫力,还能促进自身免疫病理。在实验组织培养环境中,IL-17 只是一种适度的转录激活剂。然而,IL-17 控制增强靶 mRNA 表达的转录后事件。在这里,我们发现 RNA 结合蛋白 (RBP) Arid5a(富含 AT 的相互作用结构域蛋白 5a)通过 mRNA 的转录后控制整合了多个 IL-17 驱动的信号通路。 IL-17 诱导 Arid5a 表达,Arid5a 被招募到接头 TRAF2 中。 Arid5a 通过与 3' 非翻译区结合来稳定 IL-17 诱导的细胞因子转录物,并抵消核糖核酸内切酶 MCPIP1 (Regnase-1) 介导的 mRNA 降解。 Arid5a 与真核翻译起始复合物诱导相关,并促进转录因子 (TF) IκB z ( Nfkbiz ) 和 C/EBPβ ( Cebpb ) 的翻译。这些 TF 反过来反式激活 IL-17 依赖性启动子。总之,这些数据表明 Arid5a 协调了一个前馈放大环,通过控制 mRNA 稳定性和翻译来促进 IL-17 信号传导。