Proteasomal regulation of betac 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 (Ralpha) 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 Ralpha, cytoplasmic domain, resulting in termination of signal transduction and yielding a truncated betac isoform ligated to the Ralpha 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.
Martinez-Moczygemba
M
M
Baylor College of Medicine, Departments of Medicine and Immunology, Biology of Inflammation Center, Houston, Texas 77030, USA.
Huston
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D017398:Alternative Splicing; D003546:Cysteine Endopeptidases / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000502:physiology; D005786:Gene Expression Regulation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology; D015848:Interleukin-5 / Q000494:pharmacology; D053614:Janus Kinase 2; D008894:Milk Proteins; D009097:Multienzyme Complexes / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000032:analysis; D018121:Receptors, Cytokine / Q000032:analysis / Q000502:physiology*; D018123:Receptors, Interleukin / Q000032:analysis / Q000235:genetics; D053649:Receptors, Interleukin-5; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000502:physiology; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D007377:Interleukin-3; D015848:Interleukin-5; D008894:Milk Proteins; D009097:Multienzyme Complexes; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D018121:Receptors, Cytokine; D018123:Receptors, Interleukin; D053649:Receptors, Interleukin-5; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; C114668:beta C receptor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex