Ubiquitination of the common cytokine receptor γc and regulation of expression by an ubiquitination/deubiquitination machinery

The common cytokine receptor γc is shared by the interleukin-2, -4, -7, -9, -15, and -21 receptors, and is essential for lymphocyte proliferation and survival. The regulation of γc receptor expression level is therefore critical for the ability of cells to respond to these cytokines. We previously reported that γc is efficiently constitutively internalized and addressed towards a degradation endocytic compartment. We show that γc is ubiquitinated and also associated to ubiquitinated proteins. We report that the ubiquitin-ligase c-Cbl induces γc down-regulation. In addition, the ubiquitin-hydrolase, DUB-2, counteracts the effect of c-Cbl on γc expression. We show that an increase in DUB-2 expression correlates with an increased γc half-life, resulting in the up-regulation of the receptor. Altogether, we show that γc is the target of an ubiquitination mechanism and its expression level can be regulated through the activities of a couple of ubiquitin-ligase/ubiquitin-hydrolase enzymes, namely c-Cbl/DUB-2.