The deubiquitinating enzyme DUB2A enhances CSF3 signalling by attenuating lysosomal routing of the CSF3 receptor
Ubiquitination of the CSF3R [CSF3 (colony-stimulating factor 3) receptor] occurs after activated CSF3Rs are internalized and reside in early endosomes. CSF3R ubiquitination is crucial for lysosomal routing and degradation. The E3 ligase SOCS3 (suppressor of cytokine signalling 3) has been shown to play a major role in this process. Deubiquitinating enzymes remove ubiquitin moieties from target proteins by proteolytic cleavage. Two of these enzymes, AMSH [associated molecule with the SH3 domain of STAM (signal transducing adaptor molecule)] and UBPY (ubiquitin isopeptidase Y), interact with the general endosomal sortingmachinery. Whether deubiquitinating enzymes control CSF3R trafficking from early towards late endosomes is unknown. In the present study, we asked whether AMSH, UBPY or a murine family of deubiquitinating enzymes could fulfil such a role. This DUB family (deubiquitin enzyme family) comprises four members (DUB1, DUB1A, DUB2 and DUB2A), which were originally described as being haematopoietic-specific and cytokine-inducible, but their function in cytokine receptor routing and signalling has remained largely unknown. We show that DUB2A expression is induced by CSF3 in myeloid 32D cells and that DUB2 decreases ubiquitination and lysosomal degradation of the CSF3R, leading to prolonged signalling. These results support a model in which CSF3R ubiquitination is dynamically controlled at the early endosome by feedback mechanisms involving CSF3-induced E3 ligase (SOCS3) and deubiquitinase (DUB2A) activities.
|Keywords||Deubiquitinating enzyme (DUB), Endocytosis, Granulocyte colony-stimulating factor 3 (CSF3) receptor, STAT5 protein, Signal transducer and activator of transcription (STAT) 5, Suppressor of cytokine signalling (SOCS) 3, article, bone marrow cell, colony stimulating factor receptor, colony stimulating factor receptor 3, cytokine receptor, deubiquitin enzyme family 2, endosome, enzyme activity, enzyme blood level, feedback system, human, human cell, lysosome, priority journal, protein degradation, protein expression, protein function, protein phosphorylation, protein stability, protein targeting, signal transducing adaptor protein, signal transduction, suppressor of cytokine signaling 3, ubiquitin, ubiquitination, unclassified drug|
|Persistent URL||dx.doi.org/10.1042/BJ20101628, hdl.handle.net/1765/23145|
Meenhuis, J.C.M., Verwijmeren, C., Roovers, O., & Touw, I.P.. (2011). The deubiquitinating enzyme DUB2A enhances CSF3 signalling by attenuating lysosomal routing of the CSF3 receptor. Biochemical Journal, 434(2), 343–351. doi:10.1042/BJ20101628