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IL-17-receptor-associated adaptor Act1 directly stabilizes mRNAs to mediate IL-17 inflammatory signaling
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IL-17-receptor-associated adaptor Act1 directly stabilizes mRNAs to mediate IL-17 inflammatory signaling
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Journal Article
IL-17-receptor-associated adaptor Act1 directly stabilizes mRNAs to mediate IL-17 inflammatory signaling
2018
Overview
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.
Act1 is an adaptor protein that associates with the IL-17 receptor at the cell membrane. Li and colleagues show that Act1 also exhibits unexpected RNA-binding activity and directly stabilizes select mRNAs encoding inflammatory cytokines and chemokines.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
Adaptor Proteins, Signal Transducing - immunology
/ Adaptor Proteins, Signal Transducing - metabolism
/ Animals
/ Aptamers
/ Asthma
/ Biomedical and Life Sciences
/ Gene Expression Regulation - immunology
/ Mice
/ Nuclei
/ Receptors, Interleukin-17 - metabolism
/ Signal Transduction - immunology
/ Skin
