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

Biology of Inflammation Center and Immunology, Allergy and Rheumatology Section, Department of Medicine, Baylor College of Medicine, One Baylor Plaza, BCM 285, Houston, TX 77030-3411, USA.
Journal of Leukocyte Biology (Impact Factor: 4.29). 05/2007; 81(4):1137-48. DOI: 10.1189/jlb.0706465
Source: PubMed


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, betac. Previous studies demonstrated that the ubiquitin (Ub) proteasome degradation pathway was involved in signal termination of the betac-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 betac ubiquitination and proteasome degradation but only partially required for IL-5R internalization. Furthermore, we demonstrate the direct ubiquitination of the betac cytoplasmic domain and identify lysine residues 566 and 603 as sites of betac ubiquitination. Lastly, we show that ubiquitination of the betac 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 betac tyrosine phosphorylation, ubiquitination, and IL-5R internalization. Once inside the cell, proteasomes degrade the betac 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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Available from: Jonathan Thomas Lei, Apr 22, 2015
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    • "The common beta chain shared by the cognate receptors for interleukin‐3, interleukin‐5, and the granulocyte‐macrophage colony‐stimulating factor was shown to be ubiquitinated, internalized, and degraded in a manner dependent on activity of associated JAK2 [Martinez‐Moczygemba and Huston, 2001] and, perhaps, of JAK1 that is associated with the interleukin‐5‐specific alpha chain [Martinez‐Moczygemba et al., 2007]. Similarly to the JAK‐inducible IFNAR1 ubiquitination [Kumar et al., 2007], specific ubiquitin‐ acceptor sites appear to be responsible for the downregulation of common chain induced by interleukin‐5 [Lei et al., 2011]. "
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