The RNA binding protein Insulin Growth factor 2 binding Protein 3 (IGF2BP3) modulates IL-13/IL-4 signalling in human bronchial epithelial cells and is dysregulated in type 2 disease

Abstract

Type 2 immunity encompasses the coordinated cellular responses mainly driven by IL-4 and IL-13 to target extracellular parasites. Uncontrolled, type 2 responses underpin asthma and allergy. At the cellular level, IL-13 and IL-4 bind to receptors IL-13R1 and IL-4R and trigger STAT6 phosphorylation leading to the transcription of type 2 mediators. Further regulators of this fundamental pathway remain poorly understood. We demonstrate that the RNA binding protein Insulin Growth Factor 2 Binding Protein 3 (IGF2BP3) inhibits IL-13/IL-4 effects in airway epithelium and is increased in type 2 pathology, where it correlates with an IL-13-driven signature. Mechanistically, IGF2BP3 directly binds IL4R and IL13RA1 mRNAs, which are also methylated. Depleting IGF2BP3 increased IL4R and IL13RA1 mRNAs half-life, IL-4R and IL-13R1 surface expression and IL-13/IL-4-dependent STAT6 phosphorylation. Reducing IGF2BP3 levels skewed primary airway epithelial cells towards a type 2 phenotype and enhanced IL-13-mediated transcriptional effects genome-wide. Lastly, we found IGF2BP3 levels upregulated in airway epithelium in several type 2 disease cohorts, and an IGF2BP3-dependent IL-13-driven signature predominant in type 2 high vs type 2 low asthma. Our data positions IGF2BP3 as a novel inhibitor of IL-13/IL-4 effects and type 2 disease biomarker.