Research ArticleCytokines

IL-17 integrates multiple self-reinforcing, feed-forward mechanisms through the RNA binding protein Arid5a

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Sci. Signal.  09 Oct 2018:
Vol. 11, Issue 551, eaat4617
DOI: 10.1126/scisignal.aat4617

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Stabilizing the IL-17 response

The inflammatory cytokine IL-17 can stimulate both antifungal host defense and autoimmunity by promoting the stability of target mRNAs (see the Focus by Puel and Casanova). Amatya et al. found that IL-17 increased the abundance of the RNA binding protein Arid5a in mouse cells. Loss of Arid5a decreased the cellular response to IL-17 by reducing the mRNA stability of a selection of IL-17–stimulated transcripts. For others, Arid5a instead interacted with the translation initiation factor eIF4G to augment their translation. Thus, Arid5a uses multiple posttranscriptional mechanisms to enhance IL-17 signaling.

Abstract

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.

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