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Nat Immunol. 2018 Apr;19(4):354-365. doi: 10.1038/s41590-018-0071-9. Epub 2018 Mar 21.

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

Author information

1
Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
2
Department of General Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
3
Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
4
Department of Immunology, Faculty of Biochemistry, Biophysics, and Biotechnology, Jagiellonian University, Krakow, Poland.
5
Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.
6
Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
7
Center for RNA Molecular Biology, Department of Biochemistry, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA.
8
Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
9
Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA. lix@ccf.org.

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.

PMID:
29563620
PMCID:
PMC6082628
DOI:
10.1038/s41590-018-0071-9
[Indexed for MEDLINE]
Free PMC Article

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