Proteasomal regulation of βc signaling reveals a novel mechanism for cytokine receptor heterotypic desensitization

IL-5, IL-3, and GM-CSF are hematopoietic cytokines that are key mediators of the allergic inflammatory response. The receptors for these three cytokines consist of a cytokine-specific alpha (R alpha) chain and a shared common beta (betac) chain. Herein, we demonstrate that agonistic ligation of these receptor subunits rapidly induces proteasomal degradation of the betac, but not the R alpha, cytoplasmic domain, resulting in termination of signal transduction and yielding a truncated betac isoform ligated to the R alpha subunit. Proteasomal degradation of the betac cytoplasmic domain was also a prerequisite for endocytosis and lysosomal degradation of the ligated receptor subunits. Moreover, proteasome-dependent termination of signaling induced by one betac-engaging cytokine resulted in cellular desensitization to signal transduction by subsequent stimulation with another betac-engaging cytokine. These data provide the first evidence for ligand-dependent proteasomal degradation of the betac cytoplasmic domain, and they establish a novel mechanism for heterotypic desensitization of shared cytokine receptor signaling.