FXR1 Is an IL-19-Responsive RNA-Binding Protein that Destabilizes Pro-inflammatory Transcripts in Vascular Smooth Muscle Cells

Allison B. Herman, Christine N. Vrakas, Mitali Ray, Sheri E. Kelemen, Michael J. Sweredoski, Annie Moradian, Dale S. Haines, Michael V. Autieri

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

This work identifies the fragile-X-related protein (FXR1) as a reciprocal regulator of HuR target transcripts in vascular smooth muscle cells (VSMCs). FXR1 was identified as an HuR-interacting protein by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The HuR-FXR1 interaction is abrogated in RNase-treated extracts, indicating that their association is tethered by mRNAs. FXR1 expression is induced in diseased but not normal arteries. siRNA knockdown of FXR1 increases the abundance and stability of inflammatory mRNAs, while overexpression of FXR1 reduces their abundance and stability. Conditioned media from FXR1 siRNA-treated VSMCs enhance activation of naive VSMCs. RNA EMSA and RIP demonstrate that FXR1 interacts with an ARE and an element in the 3′ UTR of TNFα. FXR1 expression is increased in VSMCs challenged with the anti-inflammatory cytokine IL-19, and FXR1 is required for IL-19 reduction of HuR. This suggests that FXR1 is an anti-inflammation responsive, HuR counter-regulatory protein that reduces abundance of pro-inflammatory transcripts. FXR1 is a muscle-enhanced and IL-19-inducible RNA-binding protein. Herman et al. show that FXR1 acts as a negative regulator of inflammatory gene expression by competing with HuR on the 3′ UTR of inflammatory mRNA transcripts. FXR1 is required for IL-19-dependent reduction of HuR mRNA stability and abundance.

Original languageEnglish
Pages (from-to)1176-1189
Number of pages14
JournalCell Reports
Volume24
Issue number5
DOIs
StatePublished - Jul 31 2018

Keywords

  • AREs
  • AU-rich elements
  • FXR1
  • HuR
  • IL-19
  • RNA stability
  • anti-inflammatory
  • inflammation

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