1. IL-17-receptor-associated adaptor Act1 directly stabilizes mRNAs to mediate IL-17 inflammatory signaling
- Author
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Jodi L. Bubenik, Xing Chen, Donny D. Licatalosi, Kommireddy Vasu, Hui Yang, Tomasz Herjan, Xiao Li, Caini Liu, Xiaoxia Li, Katarzyna Bulek, Wen Qian, Suidong Ouyang, Jun Qin, Kewal Asosingh, Paul L. Fox, Lingzi Hong, Eric Cockman, Thomas A. Hamilton, Junjie Zhao, Mark A. Aronica, Donna M. Driscoll, and Hao Zhou
- Subjects
0301 basic medicine ,Untranslated region ,Chemokine ,RNA Stability ,Immunology ,Mice ,03 medical and health sciences ,0302 clinical medicine ,P-bodies ,Animals ,Immunology and Allergy ,RNA, Messenger ,Adaptor Proteins, Signal Transducing ,Inflammation ,Messenger RNA ,Receptors, Interleukin-17 ,biology ,Chemistry ,Interleukin-17 ,Signal transducing adaptor protein ,RNA ,Translation (biology) ,MRNA stabilization ,Cell biology ,Mice, Inbred C57BL ,030104 developmental biology ,Gene Expression Regulation ,biology.protein ,Signal Transduction ,030215 immunology - 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.
- Published
- 2018
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