Lei JT, Mazumdar T, Martinez-Moczygemba M

Eosinophils are multifunctional leukocytes implicated in the pathogenesis of numerous inflammatory diseases including allergic asthma and hypereosinophilic syndrome. Eosinophil physiology is critically dependent on IL-5 and the IL-5 receptor (IL-5R), composed of a ligand binding alpha chain (IL-5R α), and a common beta chain, βc. Previously, we demonstrated ...

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that the βc cytoplasmic tail is ubiquitinated and degraded by proteasomes following IL-5 stimulation. However, a complete understanding of the role of βc ubiquitination in IL-5R biology is currently lacking. By using a well-established, stably-transduced HEK293 cell model system we show here that in the absence of ubiquitination, βc subcellular localization, IL-5 induced endocytosis, and IL-5R signaling were significantly impaired. Whereas ubiquitinated IL-5Rs internalized into recycling and trafficking endosomes for their degradation, ubiquitination-deficient IL-5Rs remained on the cell surface and displayed blunted signaling even after IL-5 stimulation. Importantly, we identified a cluster of three membrane-proximal βc lysine residues (K457, K461, and K467) whose presence was required for both JAK1/2 binding to βc and receptor ubiquitination. These findings establish that JAK kinase binding to βc requires the presence of three critical βc lysine residues, and this binding event is essential for receptor ubiquitination, endocytosis and signaling.

Date: Sep. 30, 2011

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