The deubiquitinating enzyme DUB2A enhances CSF3 signalling by attenuating lysosomal routing of CSF3 receptor

Annemarie Meenhuis , Carola Verwijmeren , Onno Roovers , Ivo Paul Touw (1)

1 Erasmus MC - Erasmus University Medical Center [Rotterdam]

Ubiquitination of the colony-stimulating factor 3 receptor (CSF3R) occurs after activated CSF3Rs are internalized and reside in early endosomes. CSF3R ubiquitination is crucial for lysosomal routing and degradation. The E3 ligase suppressor of cytokine signalling 3 (SOCS3) 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 and UBPY, 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 comprises four members (DUB1, DUB1A, DUB2, and DUB2A), which were originally described as being hematopoietic-specific and cytokine inducible, but their function in cytokine receptor routing and signalling has remained largely unknown. Here, 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 data support a model in which CSF3R receptor ubiquitination is dynamically controlled at the early endosome by feedback mechanisms involving CSF3-induced E3 ligase (SOCS3) and deubiquitinase (DUB2A) activities.

Mots clés: Life Sciences

Annemarie Meenhuis, Carola Verwijmeren, Onno Roovers, Ivo Paul Touw. The deubiquitinating enzyme DUB2A enhances CSF3 signalling by attenuating lysosomal routing of CSF3 receptor. Biochemical Journal, 2011, 434 (2), pp.343-351. ⟨10.1042/BJ20101628⟩. ⟨hal-00565907⟩