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

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, SBE (SEFIR-binding element), in the inflammatory chemokine Cxcl1 3’ UTR. mRNA-bound Act1 directs formation of three compartmentally-distinct protein-RNA 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 reduced IL-17-mediated mRNA stabilization in vitro, IL-17-induced skin inflammation and airway inflammation in a mouse asthma model, providing a therapeutic strategy for autoimmune diseases. These results reveal a network in which Act1 assembles RNPs on the 3’ UTRs of select mRNAs to control receptor-mediated mRNA stabilization and translation during inflammation.