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IL-17-receptor-associated adaptor Act1 directly stabilizes mRNAs to mediate IL-17 inflammatory signaling

Abstract

Mechanisms that degrade inflammatory mRNAs are well known; however, stabilizing mechanisms are poorly understood. Here, we show that Act1, an interleukin-17 (IL-17)-receptor-complex adaptor, binds and stabilizes mRNAs encoding key inflammatory proteins. The Act1 SEFIR domain binds a stem-loop structure, the SEFIR-binding element (SBE), in the 3′ untranslated region (UTR) of Cxcl1 mRNA, encoding an inflammatory chemokine. mRNA-bound Act1 directs formation of three compartmentally distinct RNA–protein complexes (RNPs) that regulate three disparate events in inflammatory-mRNA metabolism: preventing mRNA decay in the nucleus, inhibiting mRNA decapping in P bodies and promoting translation. SBE RNA aptamers decreased IL-17-mediated mRNA stabilization in vitro, IL-17-induced skin inflammation and airway inflammation in a mouse asthma model, thus providing a therapeutic strategy for autoimmune diseases. These results reveal a network in which Act1 assembles RNPs on the 3′ UTRs of select mRNAs and consequently controls receptor-mediated mRNA stabilization and translation during inflammation.

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Fig. 1: IL-17A induces distinct Act1 RNPs in the nucleus and cytoplasmic granules.
Fig. 2: Act1 directly binds the CXCL1 3′ UTR through the SEFIR domain.
Fig. 3: Act1 SEFIR binds a stem-loop structure in the Cxcl1 3′ UTR.
Fig. 4: Act1 RNA binding to the 3′ UTR inhibits decapping through TBK1-mediated phosphorylation of Dcp1.
Fig. 5: Act1 forms distinct RNPs with Dcp1, Dcp2, SF2 and HuR.
Fig. 6: SBE RNA aptamers abolished IL-17A-induced mRNA stabilization of Cxcl1, Csf2 and Tnf.
Fig. 7: SBE RNA aptamers inhibited IL-17A-dependent skin hyperplasia and HDM-induced airway inflammation.

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Acknowledgements

We thank J. Lykke-Andersen (University of California, San Diego) as well as V. Heissmeyer (Biomedical Center Munich) and M. Kiledjian (Rutgers University) for plasmids. We thank T. Maniatis (Columbia University Medical Center) and E. Izaurralde (Max Planck Institute for Developmental Biology) for providing materials. This work was supported by the US National Institutes of Health (P01HL103453, P01 CA062220 to X.L. and P01 HL 029582 to P.L.F/X.L.) and a grant from NMSS (RG5130A2/1 to X.L.).

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T.H. and L.H. designed experiments, performed experiments, analyzed data and wrote the manuscript with input from the coauthors. J.B., K.B., W.Q., C.L., Xiao Li, X.C., H.Y., S.O., H.Z., J.Z., V.K. and E.C. assisted with experiments and participated in discussion. M.A., K.A., D.D.L., J.Q., P.L.F. and T.A.H. facilitated the experimentation and offered critical scientific discussion. Xiaoxia Li and D.D. designed experiments, analyzed data and wrote the manuscript with input from the coauthors.

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Correspondence to Xiaoxia Li.

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Herjan, T., Hong, L., Bubenik, J. et al. IL-17-receptor-associated adaptor Act1 directly stabilizes mRNAs to mediate IL-17 inflammatory signaling. Nat Immunol 19, 354–365 (2018). https://doi.org/10.1038/s41590-018-0071-9

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