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 sorting machinery. 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.
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Research Article|
February 11 2011
The deubiquitinating enzyme DUB2A enhances CSF3 signalling by attenuating lysosomal routing of the CSF3 receptor
Annemarie Meenhuis;
Annemarie Meenhuis
1Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands
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Carola Verwijmeren;
Carola Verwijmeren
1Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands
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Onno Roovers;
Onno Roovers
1Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands
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Ivo P. Touw
Ivo P. Touw
1
1Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands
1To whom correspondence should be addressed (email i.touw@erasmusmc.nl).
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Publisher: Portland Press Ltd
Received:
October 04 2010
Revision Received:
November 22 2010
Accepted:
December 15 2010
Accepted Manuscript online:
December 15 2010
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2011 Biochemical Society
2011
Biochem J (2011) 434 (2): 343–351.
Article history
Received:
October 04 2010
Revision Received:
November 22 2010
Accepted:
December 15 2010
Accepted Manuscript online:
December 15 2010
Citation
Annemarie Meenhuis, Carola Verwijmeren, Onno Roovers, Ivo P. Touw; The deubiquitinating enzyme DUB2A enhances CSF3 signalling by attenuating lysosomal routing of the CSF3 receptor. Biochem J 1 March 2011; 434 (2): 343–351. doi: https://doi.org/10.1042/BJ20101628
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