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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 3

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IL-5 regulation of transmembrane IL-5Rα and sIL-5Rα expression. (a) TF1 ...
IL-5 regulation of transmembrane IL-5Rα and sIL-5Rα expression. (a) TF1 cells (107/lane) were cytokine-starved for 48 hours and stimulated with 5 ng/ml human IL-5 for the indicated times. Whole-cell lysates were prepared and subjected to IP/IB with anti–IL-5Rα antibodies. The top arrow represents IL-5Rα (60 kDa), and the bottom arrow corresponds to sIL-5Rα (50 kDa). The multiple bands represent differential glycosylation (see below). (b) TF1 cells continuously cultured in IL-5 were immunoprecipitated with anti–IL-5Rα antibodies (lanes 1 and 2), and either left untreated (lane 1) or treated with PNGase F (lane 2) for 1–2 hours to remove N-linked glycosyl groups. Lanes 3 and 4 are controls for sIL-5Rα migration, using 20 ng of baculovirus-expressed, recombinant sIL-5Rα protein (brsIL-5Rα), which was either untreated (lane 3) or treated with PNGase F (lane 4) for 1–2 hours, separated by 12.5% SDS-PAGE, and immunoblotted with anti–IL-5Rα antibodies. Note how the multiple bands in lane 1 resolve to two distinct bands in lane 2 (PNGase F–treated). (c) TF1 cells (107/lane) were cytokine-starved for 48 hours and stimulated with 5 ng/ml IL-5 for the indicated times. Total RNA was prepared for each timepoint, and 30 μg of RNA/lane were analyzed with a probe specific to the extracellular domain of IL-5Rα (detects both isoforms). GAPDH was used as an internal control.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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