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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / immunology
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Gene Expression Regulation / immunology
  • Inflammation / immunology*
  • Inflammation / metabolism
  • Interleukin-17 / immunology
  • Interleukin-17 / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • RNA Stability / physiology*
  • RNA, Messenger / metabolism
  • Receptors, Interleukin-17 / metabolism
  • Signal Transduction / immunology*

Substances

  • Adaptor Proteins, Signal Transducing
  • Interleukin-17
  • RNA, Messenger
  • Receptors, Interleukin-17
  • Traf3ip2 protein, mouse