Detrimental ELAVL-1/HuR-dependent GSK3beta mRNA stabilization impairs resolution in acute respiratory distress syndrome

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) 3beta during ARDS via inhibition of alveolar epithelial protein transport. We hypothesized that post-transcriptional regulation of GSK3beta 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 GSK3beta messenger RNA utilizing two lung cancer cell line array datasets. Among potential regulatory partners of GSK3beta, these studies identified the RNA-binding protein ELAVL-1/HuR (Embryonic Lethal, Abnormal Vision, Drosophila-Like) as a central component in a likely GSK3beta 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 GSK3beta 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 GSK3beta 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 GSK3beta. Together, our findings indicate a previously unknown interaction between GSK3beta and ELAV-1 during ARDS, and suggest the inhibition of the ELAV-1- GSK3beta pathways as a novel ARDS treatment approach.

• Hoffman, O.
• Burns, N.
• Vadasz, I.
• Eltzschig, H. K.
• Edwards, M. G.
• Vohwinkel, C. U.