JAK kinases control IL-5 receptor ubiquitination, degradation, and internalization

Margarita Martinez-Moczygemba, David P. Huston, Jonathan T. Lei

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

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 α chain and a shared signaling chain, βc. Previous studies demonstrated that the ubiquitin (Ub) proteasome degradation pathway was involved in signal termination of the βc-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 βc ubiquitination and proteasome degradation but only partially required for IL-5R internalization. Furthermore, we demonstrate the direct ubiquitination of the βc cytoplasmic domain and identify lysine residues 566 and 603 as sites of βc ubiquitination. Lastly, we show that ubiquitination of the βc 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 βc tyrosine phosphorylation, ubiquitination, and IL-5R internalization. Once inside the cell, proteasomes degrade the βc 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.

Original languageEnglish (US)
Pages (from-to)1137-1148
Number of pages12
JournalJournal of Leukocyte Biology
Volume81
Issue number4
DOIs
StatePublished - Apr 2007

Keywords

  • βc-sharing receptors
  • Endocytosis
  • Eosinophils
  • Hematopoietic cytokines
  • Signal transduction

ASJC Scopus subject areas

  • Cell Biology

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