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

N Amatya, EE Childs, JA Cruz, FEY Aggor, AV Garg… - Science …, 2018 - science.org
Science Signaling, 2018science.org
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 …
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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