Arid5a orchestrates IL-17-mediated inflammation through post-transcriptional control of mRNA

Abstract Interleukin-17A (IL-17) is a proinflammatory cytokine essential for clearance of microbial pathogens, but conversely drives immunopathology in autoimmune settings. Surprisingly, very little is known about IL-17 receptor-mediated signaling pathway. Although IL-17 is consistently found to be a modest activator of gene transcription in experimental settings, its biological impact in vivo is profound. In addition to de novo transcription, IL-17 also upregulates inflammatory gene expression by stabilizing their transcripts. mRNA stabilization is a central, but still poorly understood facet of IL-17 signaling. Here, we report an RNA binding protein Arid5a (AT-rich interactive domain-containing protein 5A) as a novel mediator of IL-17-induced stabilization of inflammatory mRNAs. IL-17 stimulation upregulated Arid5a expression, whereupon Arid5a was rapidly recruited to TRAF2. Arid5a stabilized multiple IL-17-induced cytokine mRNA transcripts, including Il6, Cxcl1 and Cxcl5, by binding to their 3′ untranslated regions (UTR). In some cases, Arid5a counteracted mRNA degradation mediated by the endoribonuclease MCPIP1 (Regnase-1). Additionally, Arid5a enhanced IL-17-induced expression of the transcription factors IκBz (Nfkbiz) and C/EBPβ (Cebpb), which could then transactivate IL-17-dependent promoters. Arid5a bound to Nfkbiz or Cebpb transcripts, but surprisingly did not detectably affect total Nfkbiz or Cebpb mRNA levels. Rather, Arid5a facilitated translation of IkBz and C/EBPb. Thus, Arid5a orchestrates a feed-forward amplification loop within the IL-17 pathway, revealing a new function for Arid5a in controlling translation and demonstrating a role in controlling downstream IL-17 signaling.