RT Journal Article
SR Electronic
T1 IL-17 integrates multiple self-reinforcing, feed-forward mechanisms through the RNA binding protein Arid5a
JF Science Signaling
JO Sci. Signal.
FD American Association for the Advancement of Science
SP eaat4617
DO 10.1126/scisignal.aat4617
VO 11
IS 551
A1 Amatya, Nilesh
A1 Childs, Erin E.
A1 Cruz, J. Agustin
A1 Aggor, Felix E. Y.
A1 Garg, Abhishek V.
A1 Berman, Andrea J.
A1 Gudjonsson, Johann E.
A1 Atasoy, Ulus
A1 Gaffen, Sarah L.
YR 2018
UL http://stke.sciencemag.org/content/11/551/eaat4617.abstract
AB 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.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.