The two subunits of the interleukin-4 receptor mediate independent and distinct patterns of ligand endocytosis

Interleukin-4 (IL-4) triggers cellular responses by interaction with the bi partite interleukin-4 receptor (IL-4R). IL-4-responsive cells specifically endocytose IL-4. We studied the ligand internalization properties of the hu man IL-4R and analyzed the specific functions of its two subunits IL-4R alp ha and gamma c in this process. IL-4 mutant RY, which binds to IL-4R alpha but does not recruit ye into the receptor complex was used as a tool to sho w that IL-4R alpha can promote independent ligand uptake in human T cells. Internalization was limited, however, by rapid IL-4 dissociation, suggestin g that one important function of gamma c in IL-4 endocytosis is to retain t he ligand sufficiently long within the ternary receptor complex. We then me asured IL-4 internalization by murine Ba/F3 cells that were stably transfec ted with various human IL-4R constructs. Efficient IL-4 uptake required the cytoplasmic section of the receptor. The intracellular domains of IL-4R al pha and gamma c were responsible for independent endocytosis processes with distinct kinetics, IL-4R alpha mediated internalization resulted in long-t erm intracellular maintainance of IL-4, whereas gamma c directed the associ ated radioligand to intracellular breakdown and rapid release in the form o f degraded protein. Mutants of either IL-4R subunit deficient in Janus kina se activation were not impaired in internalization, indicating that IL-4 en docytosis is not functionally connected to signal transduction.