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

Abstract

Interleukin-17A 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 post-transcriptional 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 post-transcriptional 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) IκBξ (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.

The role of interleukin-17 in tumor development and progression

“…The posttranscriptional regulation of mRNA is part of a self-reinforcing and feedforward mechanism that potentiates IL-17 activity. This is illustrated by IL-17-induced expression of Arid5a, which in turn counteracts ribonucleasemediated degradation of labile transcripts and promotes mRNA translation (Amatya et al, 2018). A set of RNA destabilizers, including SF2, Dcp1/2, Regnase-1, and Roquins, has been shown to balance IL-17-mediated mRNA stabilization.…”

IL-17A inhibition by secukinumab induces early clinical, histopathologic, and molecular resolution of psoriasis

“…In it, T H 17-derived IL-17A and IL-17F induce massive overproduction of inflammatory products, such as IL-17C, IL-36, IL-19, CCL20, CXCL chemokines, and S100 proteins, in psoriatic KCs, in turn altering resident skin cell homeostasis and further attracting activated leukocyte subsets to maintain plaques. 7,16,17 KC-produced IL-17C is capable of further amplification of this immune circuit by activating T H 17 cells to secrete more IL-17A. 18 Support for systemic feed-forward inflammation originated from studies in transgenic mice: misexpressing inflammatory products in KCs led to increases in vascular inflammation, arthritis, and soluble mediators in the circulation.…”

Post‐transcriptional control of immune responses and its potential application

“…It is also reported that Arid5a binds to T‐box‐containing protein expressed in T cells (T‐bet) and signal transducer and activator of transcription 3 (Stat3) mRNA to enhance the inflammation . Moreover, Arid5a is reported to promote translation of Nfkbiz and Cebpb mRNA . Thus, these studies demonstrate that Arid5a is a positive regulator of immune responses which antagonises Regnase‐1 function.…”

“…43,44 Moreover, Arid5a is reported to promote translation of Nfkbiz and Cebpb mRNA. 45 Thus, these studies demonstrate that Arid5a is a positive regulator of immune responses which antagonises Regnase-1 function. It would be interesting to globally identify Arid5a binding sites at a transcriptome-wide level to gain insights into its binding motifs and to compare them with those of Regnase-1 and Roquin.…”