Allergic respiratory diseases are characterized by large numbers of eosinophils and their reactive products in the airways and blood. IL-5 is the principal cytokine for eosinophil differentiation, activation, and survival. IL-5 initiates its biological effects by binding to the IL-5 receptor which is composed of a ligand specific IL-5 receptor alpha chain (IL-5R?) and a shared signaling component, ?c. Our previous studies revealed that IL-5 receptor signaling is partially terminated by ubiquitin/proteasome degradation of the ?c cytoplasmic domain, followed by lysosomal degradation of the remaining truncated IL-5R complex. However, the molecular details underlying IL-5R internalization and endocytic trafficking remain largely unknown. Since IL-5 and its cognate receptor are critical for eosinophil biology, understanding how to extinguish inflammatory signals induced by this cytokine is essential for preventing a protective response from causing injury to the host. Furthermore, dissecting the mechanisms regulating eosinophil biology has importance for the development of novel approaches to modulate IL-5-mediated inflammation.
The research focus of our laboratory is to understand the molecular mechanisms controlling interleukin-5 receptor endocytosis and signal termination. Currently, we are investigating how the ubiquitin/proteasome degradation pathway controls the endocytic trafficking of the IL-5 receptor, and how this process contributes to “shutting off” IL-5-mediated signaling. In a related project, we aim to understand the significance of differential compartmentalization of the IL-5R into lipid rafts and clathrin-containing vesicles.