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Sci Signal. 2018 Oct 9;11(551). pii: eaat4617. doi: 10.1126/scisignal.aat4617.

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

Author information

1
Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
2
Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA.
3
Department of Dermatology, Taubman Center, University of Michigan, Ann Arbor, MI 48109, USA.
4
Division of Allergy and Immunology, University of Michigan, Ann Arbor, MI 48109, USA.
5
Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA. sarah.gaffen@pitt.edu.

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.

PMID:
30301788
PMCID:
PMC6188668
[Available on 2019-10-09]
DOI:
10.1126/scisignal.aat4617

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