Regulation of Interleukin-10 Receptor Ubiquitination and Stability by Beta-TrCP-Containing Ubiquitin E3 Ligase
Figure 7
The major findings of the present study are summarized in a model.
IL-10R1 contains two βTrCP-binding sites (318DSGFGS and 368DSGICLQEP) in its cytoplasmic tail (see the dash-lined box marked by ‘Zoom-in 1’). The phosphorylation of the serine residues within these two sites can additively trigger recruitment of SCFβTrCP ubiquitin E3 ligase, resulting in ubiquitination of cell surface IL-10R1 (see the dash-lined boxes marked by ‘Zoom-in 2’). The ubiquitination of IL-10R1 promotes its endocytosis that expedites the latter’s eventual degradation via the lysosome. The nature of the physiologically relevant stimuli and of the associated kinase(s) that trigger phophorylation of the two βTrCP-binding sites within IL-10R1 is not known at this point. Nevertheless, in ectopically transfected IL-10R1, these sites appear to be both engaged, which results in the negative regulation of cell surface IL-10R1 levels. Potentially, under certain physiological/pathological conditions that trigger DSG motifs phosphorylation, the βTrCP-mediated regulation of cell surface IL-10R1 may play an important role in determining the magnitude of IL-10-mediated Jak/Stat signaling and transcriptional regulation.