HuR is required for IL-17-induced Act1-mediated CXCL1 and CXCL5 mRNA stabilization

J Immunol. 2013 Jul 15;191(2):640-9. doi: 10.4049/jimmunol.1203315. Epub 2013 Jun 14.

Abstract

IL-17, a major inflammatory cytokine plays a critical role in the pathogenesis of many autoimmune inflammatory diseases. In this study, we report a new function of RNA-binding protein HuR in IL-17-induced Act1-mediated chemokine mRNA stabilization. HuR deficiency markedly reduced IL-17-induced chemokine expression due to increased mRNA decay. Act1-mediated HuR polyubiquitination was required for the binding of HuR to CXCL1 mRNA, leading to mRNA stabilization. Although IL-17 induced the coshift of Act1 and HuR to the polysomal fractions in a sucrose gradient, HuR deficiency reduced the ratio of translation-active/translation-inactive IL-17-induced chemokine mRNAs. Furthermore, HuR deletion in distal lung epithelium attenuated IL-17-induced neutrophilia. In summary, HuR functions to couple receptor-proximal signaling to posttranscriptional machinery, contributing to IL-17-induced inflammation.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Cell Line
  • Chemokine CXCL1 / genetics*
  • Chemokine CXCL5 / genetics*
  • ELAV Proteins / genetics
  • ELAV Proteins / metabolism*
  • HeLa Cells
  • Humans
  • Inflammation / immunology
  • Interleukin-17 / metabolism*
  • Lung / metabolism
  • Mice
  • Mice, Knockout
  • Protein Binding
  • RNA Stability*
  • RNA, Messenger / metabolism
  • Respiratory Mucosa / metabolism
  • Signal Transduction
  • Ubiquitination

Substances

  • Adaptor Proteins, Signal Transducing
  • Chemokine CXCL1
  • Chemokine CXCL5
  • Cxcl1 protein, mouse
  • Cxcl5 protein, mouse
  • ELAV Proteins
  • Interleukin-17
  • RNA, Messenger
  • Traf3ip2 protein, mouse