title: Detrimental ELAVL-1/HuR-dependent GSK3β mRNA stabilization impairs resolution in acute respiratory distress syndrome.
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.
authors.affiliation: Department of Pediatrics, University of Colorado at Denver, Aurora, Colorado, United States of America.
authors.forename: Olivia
authors.initials: O
authors.lastname: Hoffman
authors.affiliation: Developmental Lung Biology, Cardio Vascular Pulmonary Research Laboratories, Division of Pulmonary Sciences and Critical Care Medicine, Division of Pediatric Critical Care, Departments of Medicine and Pediatrics, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: Nana
authors.initials: N
authors.lastname: Burns
authors.affiliation: Department of Internal Medicine, Justus Liebig University, Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Giessen, Germany.
authors.forename: István
authors.initials: I
authors.lastname: Vadász
authors.affiliation: Organ Protection Program, Department of Anesthesiology, University of Colorado, School of Medicine, Aurora, Colorado, United States of America.
authors.forename: Holger K
authors.initials: HK
authors.lastname: Eltzschig
authors.affiliation: Developmental Lung Biology, Cardio Vascular Pulmonary Research Laboratories, Division of Pulmonary Sciences and Critical Care Medicine, Division of Pediatric Critical Care, Departments of Medicine and Pediatrics, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Edwards
authors.affiliation: Department of Pediatrics, University of Colorado at Denver, Aurora, Colorado, United States of America.|Developmental Lung Biology, Cardio Vascular Pulmonary Research Laboratories, Division of Pulmonary Sciences and Critical Care Medicine, Division of Pediatric Critical Care, Departments of Medicine and Pediatrics, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: Christine U
authors.identifier: http://orcid.org/0000-0001-8959-157X
authors.initials: CU
authors.lastname: Vohwinkel
mesh_terms: D000072283:A549 Cells; D000818:Animals; D004195:Disease Models, Animal; D000067780:ELAV-Like Protein 1 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006851:Hydrochloric Acid / Q000633:toxicity; D051379:Mice; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D012128:Respiratory Distress Syndrome / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; C000593997:Elavl1 protein, mouse; D012333:RNA, Messenger; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D006851:Hydrochloric Acid