Journal
JOURNAL OF LEUKOCYTE BIOLOGY
Volume 81, Issue 4, Pages 1137-1148Publisher
WILEY
DOI: 10.1189/jlb.0706465
Keywords
signal transduction; endocytosis; beta c-sharing receptors; hematopoietic cytokines; eosinophils
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Funding
- NIAID NIH HHS [AI 50686, AI 063178-01, AI 36936] Funding Source: Medline
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IL-5, IL-3, and GM-CSF are related hematopoietic cytokines, which regulate the function of myeloid cells and are mediators of the allergic inflammatory response. These cytokines signal through heteromeric receptors containing a specific alpha chain and a shared signaling chain, beta e. Previous studies demonstrated that the ubiquitin (Ub) proteasome degradation pathway was involved in signal termination of the beta c-sharing receptors. In this study, the upstream molecular events leading to proteasome degradation of the IL-5 receptor (IL-5R) were examined. By using biochemical and flow cytometric methods, we show that JAK kinase activity is required for beta c ubiquitination and proteasome degradation but only partially required for IL-5R internalization. Furthermore, we demonstrate the direct ubiquitination of the Pc cytoplasmic domain and identify lysine residues 566 and 603 as sites of Pe ubiquitination. Lastly, we show that ubiquitination of the Pc cytoplasmic domain begins at the plasma membrane, increases after receptor internalization, and is degraded by the proteasome after IL-5R internalization. We propose an updated working model of IL-5R down-regulation, whereby IL-5 ligation of its receptor activates JAK2/1 kinases, resulting in Pc tyrosine phosphorylation, ubiquitination, and IL-5R internalization. Once inside the cell, proteasomes degrade the Pc cytoplasmic domain, and the truncated receptor complex is terminally degraded in the lysosomes. These data establish a critical role for JAK kinases and the Ub/proteasome degradation pathway in IL-5R down-regulation.
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