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

Type 2 immune responses are mainly driven by interleukins (IL)-4 and -13. Typically directed against extracellular pathogens, type 2 immunity is dysregulated in allergic diseases. IL-4 and IL-13 signal via type I and II receptors; while IL-4 can bind to type I (heterodimers of IL-4R and common gamma chain) and type II receptors (heterodimers of IL-4R and IL-13Rα1), IL-13 solely binds to type II receptors in non-hematopoietic cells such as airways epithelium. Airway epithelial cells sit at the interface between tissue and environment, where IL-13/IL-4 binding triggers the phosphorylation of signal transducer and activator of transcription 6 (STAT6) leading to increased transcription of mucosal mediators that initiate type 2 responses in the underlying tissue. Further regulators of this fundamental pathway remain poorly understood. Here we detect the presence of RNA binding protein Insulin Growth factor 2 binding Protein 3 (IGF2BP3), considered an oncofoetal factor, in healthy human airway epithelium. We found IGF2BP3 directly bound to IL4R and IL13RA1 mRNAs. Depletion of IGF2BP3 led to an increase of IL4R and IL13RA1 mRNA half-life and IL-4Rα and IL-13Rα1 cell surface expression, without affecting IL4R or IL13RA1 mRNA levels, in human bronchial epithelial BEAS-2B cells. Concomitantly, IGF2BP3 depletion led to increased IL-13/IL-4-dependent STAT6 phosphorylation and activity as determined by increased expression of IL-13/IL-4-dependent eotaxins CCL26, CCL24 and CCL11 mRNAs, and the Th2-archetypal factor GATA3 mRNA. We recapitulated IGF2BP3 effects in human primary airway cells. Subcellular fractionation and RNA-sequencing (Frac-seq) showed that decreasing IGF2BP3 levels augmented IL-13-mediated effects on steady mRNA levels. Lastly, we found IGF2BP3 expression upregulated in airway epithelium in several cohorts of type 2 diseases, and a signature of IGF2BP3-dependent IL-13-driven genes predominant in type 2 high vs type 2 low asthma. Our work shows for the first time that RNA binding proteins can modulate IL-13/IL-4 signalling and that IGF2BP3 suppresses type 2-dependent signalling in human bronchial epithelium. Patients with type 2 disease present increased IGF2BP3 levels and an increased signature of IL-13-driven and IGF2BP3-dependent genes, positioning IGF2BP3 as a novel biomarker of type 2 disease and IL-13-driven pathology.