Interleukin 17 (IL-17) promotes the expression of chemokines and cytokines via the induction of gene transcription and post-transcriptional stabilization of mRNA. We show here that IL-17 enhanced the stability of chemokine CXCL1 mRNA and other mRNAs through a pathway that involved the adaptor Act1, the adaptors TRAF2 or TRAF5 and the splicing factor SF2 (also known as alternative splicing factor (ASF)). TRAF2 and TRAF5 were necessary for IL-17 to signal the stabilization of CXCL1 mRNA. Furthermore, IL-17 promoted the formation of complexes of TRAF5-TRAF2, Act1 and SF2 (ASF). Overexpression of SF2 (ASF) shortened the half-life of CXCL1 mRNA, whereas depletion of SF2 (ASF) prolonged it. SF2 (ASF) bound chemokine mRNA in unstimulated cells, whereas the SF2 (ASF)-mRNA interaction was much lower after stimulation with IL-17. Our findings define an IL-17-induced signaling pathway that links to the stabilization of selected mRNA species through Act1, TRAF2-TRAF5 and the RNA-binding protein SF2 (ASF).
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We thank H. Nakano (Juntendo University School of Medicine) for MEFs deficient in both TRAF2 and TRAF5 and reconstituted TRAF2- and TRAF5-deficient MEFs; and X. Fu (University of California, San Diego) for inducible Tet-Off SF2 (ASF) MEFs. Supported by the US Public Health Service (R01CA039621 to T.H. and R01HL098935 to X.L.), the American Asthma Foundation (X.L.) and the David and Lindsay Morgenthaler Endowment (D.S.).
The authors declare no competing financial interests.
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