Detrimental ELAVL-1/HuR-dependent GSK3β mRNA stabilization impairs resolution in acute respiratory distress syndrome

Olivia Hoffman, Nana Burns, István Vadász, Holger K. Eltzschig, Michael G. Edwards, Christine U. Vohwinkel

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

A hallmark of acute respiratory distress syndrome (ARDS) is accumulation of protein-rich edema in the distal airspaces and its removal is critical for patient survival. Previous studies have shown a detrimental role of Glycogen Synthase Kinase (GSK) 3β during ARDS via inhibition of alveolar epithelial protein transport. We hypothesized that post-transcriptional regulation of GSK3β could play a functional role in ARDS resolution. To address this hypothesis, we performed an in silico analysis to identify regulatory genes whose expression correlation to GSK3β messenger RNA utilizing two lung cancer cell line array datasets. Among potential regulatory partners of GSK3β, these studies identified the RNA-binding protein ELAVL-1/HuR (Embryonic Lethal, Abnormal Vision, Drosophila-Like) as a central component in a likely GSK3β signaling network. ELAVL-1/HuR is a RNA-binding protein that selectively binds to AU-rich elements of mRNA and enhances its stability thereby increasing target gene expression. Subsequent studies with siRNA suppression of ELAVL-1/HuR demonstrated deceased GSK3β mRNA and protein expression and improved clearance of FITC-albumin in A549 cells. Conversely, stabilization of ELAVL-1/HuR with the proteasome inhibitor MG-132 resulted in induction of GSK3β at mRNA and protein level and attenuated FITC-albumin clearance. Utilizing ventilator-induced lung injury or intra-tracheal installation of hydrochloric acid to induce ARDS in mice, we observed increased mRNA and protein expression of ELAVL-1/HuR and GSK3β. Together, our findings indicate a previously unknown interaction between GSK3β and ELAV-1 during ARDS, and suggest the inhibition of the ELAV-1- GSK3β pathways as a novel ARDS treatment approach.

Original languageEnglish (US)
Article numbere0172116
JournalPloS one
Volume12
Issue number2
DOIs
StatePublished - Feb 1 2017
Externally publishedYes

Fingerprint

Adult Respiratory Distress Syndrome
Stabilization
Messenger RNA
RNA-Binding Proteins
RNA-binding proteins
Proteins
Gene expression
AU Rich Elements
albumins
Glycogen Synthase Kinase 3
protein synthesis
Ventilator-Induced Lung Injury
Proteasome Inhibitors
Hydrochloric Acid
Gene Expression
ventilators
gene expression
protein transport
hydrochloric acid
Small Interfering RNA

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Detrimental ELAVL-1/HuR-dependent GSK3β mRNA stabilization impairs resolution in acute respiratory distress syndrome. / Hoffman, Olivia; Burns, Nana; Vadász, István; Eltzschig, Holger K.; Edwards, Michael G.; Vohwinkel, Christine U.

In: PloS one, Vol. 12, No. 2, e0172116, 01.02.2017.

Research output: Contribution to journalArticle

Hoffman, Olivia ; Burns, Nana ; Vadász, István ; Eltzschig, Holger K. ; Edwards, Michael G. ; Vohwinkel, Christine U. / Detrimental ELAVL-1/HuR-dependent GSK3β mRNA stabilization impairs resolution in acute respiratory distress syndrome. In: PloS one. 2017 ; Vol. 12, No. 2.
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