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

Margarita Martinez-Moczygemba, David P. Huston

Research output: Contribution to journalArticle

38 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1797-1806
Number of pages10
JournalJournal of Clinical Investigation
Volume108
Issue number12
DOIs
StatePublished - 2001

ASJC Scopus subject areas

  • Medicine(all)

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