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Proteasomal regulation of βc signaling reveals a novel mechanism for cytokine receptor heterotypic desensitization
Margarita Martinez-Moczygemba, David P. Huston
Margarita Martinez-Moczygemba, David P. Huston
Published December 15, 2001
Citation Information: J Clin Invest. 2001;108(12):1797-1806. https://doi.org/10.1172/JCI13877.
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Article

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

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Abstract

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 α (Rα) chain and a shared common β (βc) chain. Herein, we demonstrate that agonistic ligation of these receptor subunits rapidly induces proteasomal degradation of the βc, but not the Rα, cytoplasmic domain, resulting in termination of signal transduction and yielding a truncated βc isoform ligated to the Rα subunit. Proteasomal degradation of the βc 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 βc-engaging cytokine resulted in cellular desensitization to signal transduction by subsequent stimulation with another βc-engaging cytokine. These data provide the first evidence for ligand-dependent proteasomal degradation of the βc cytoplasmic domain, and they establish a novel mechanism for heterotypic desensitization of shared cytokine receptor signaling.

Authors

Margarita Martinez-Moczygemba, David P. Huston

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Figure 6

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IL-5 stimulation results in cellular refractoriness to other βc-engaging...
IL-5 stimulation results in cellular refractoriness to other βc-engaging cytokines. (a) TF1 cells that had been cytokine-starved for 24 hours were unstimulated (lane 1), or were stimulated with 20 ng/ml IL-5 for 5 minutes (lane 2) or 1 hour (lane 3). After 1 hour of incubation in IL-5, cells in lane 4 were harvested, washed once in 1× PBS (to remove IL-5), and restimulated with 20 ng/ml IL-3 for 5 minutes. As a positive control (lane 5), cells were stimulated only with 20 ng/ml IL-3 for 5 minutes. Whole-cell lysates were prepared and immunoprecipitated with anti-βc monoclonal antibody and immunoblotted with monoclonal antibody 4G10 (upper panel). The membrane was stripped and reprobed with anti-βc polyclonal antibodies (bottom panel). The migration of βc and βIP are indicated. (b) Same as in a, except that cells were pretreated with 20 ng/ml GM-CSF for 5 minutes or 1 hour, washed once in 1× PBS (to remove GM-CSF), and restimulated with 20 ng/ml IL-5 for 5 minutes. As a positive control (lane 5), cells were stimulated with 20 ng/ml IL-5 for 5 minutes only.

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