Dysregulation of ZFP36L1 and ZFP36L2 in asthma alters epithelial integrity and genome-wide glucocorticoid responses

Background: Asthma is the most common chronic inflammatory disease of the airways. ~4% of patients have severe asthma, which remains uncontrolled despite treatment with steroids. The inflammatory profile of these patients has been extensively characterised; however, mechanisms underpinning severe asthma epithelial biology remain poorly understood. Aim: To determine the role of RNA binding proteins (RBPs) in epithelium integrity and glucocorticoid responses in asthma. Results: Employing Frac-seq (subcellular fractionation and RNA-seq) in primary bronchial epithelial cells (BECs) from healthy controls (HC) and severe asthma patients (SA) allowed us to discover a genome-wide disconnection between differences in transcription vs translation in asthma. Our data show that the RBPs ZFP36L1/L2 are downregulated in human severe asthma and a mouse asthma model, while upregulated by glucocorticoids. Glucocorticoids, classic ‘transcriptional mediators’, modulate both transcription as well as ribosome binding of mRNAs, and their effects are ZFP36L1/L2-dependent. Genes related to epithelium integrity such as keratins being modulated by ZFP36L1/L2 at the level of mRNA translation. Conclusions: Dysregulation of ZFP36L1/L2 in severe asthma epithelium contributes to glucocorticoid non-responsiveness as well as epithelial barrier disruption.