Regulation of myelopoiesis through syntenin-mediated modulation of IL-5 receptor output.
The granulocyte-macrophage colony-stimulating factor (GM-CSF)/interleukin (IL)-3/IL-5 receptor family regulates the production and function of myeloid cells. These cytokines signal through receptor complexes that consist of unique ligand-binding alpha-chains and common signaling beta-chains. IL-5 is distinct from IL-3 and GM-CSF in its capacity to induce eosinophil development, however, the molecular mechanisms that generate functional diversity within this receptor family are mostly unknown. Here, we characterized the selective IL-5Ralpha-binding adapter protein syntenin in IL-5R function. Syntenin and IL-5Ralpha colocalize at the plasma membrane and in early endosomal compartments. Manipulation of syntenin expression by ectopic expression or knockdown selectively modulated IL-5R but not GM-CSF receptor signaling, and severely affected IL-5-induced eosinophil differentiation from primary human CD34+ hematopoietic progenitor cells. We found syntenin up-regulated during eosinophilopoiesis but down-regulated during neutropoiesis. Syntenin forms complexes with multiple IL-5Ralpha chains, suggesting that syntenin-enhanced IL-5R output may result from stabilization of an IL-5-induced oligomeric receptor complex. These data demonstrate that cytokine-specific functions can be transduced by unique receptor alpha-chain-associating adapter proteins.
Beekman
Jeffrey M
JM
Molecular Immunology Laboratory, Department of Immunology, Wilhelmina Childrens Hospital, University Medical Centre Utrecht, Utrecht, The Netherlands.
Verhagen
Liesbeth P
LP
Geijsen
Niels
N
Coffer
Paul J
PJ
D018952:Antigens, CD34; D002454:Cell Differentiation / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism*; D004804:Eosinophils / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D018922:HL-60 Cells; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D053666:Interleukin-5 Receptor alpha Subunit / Q000378:metabolism*; D038042:Myelopoiesis / Q000502:physiology*; D055550:Protein Stability; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D053676:Syntenins / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology
D018952:Antigens, CD34; C485918:IL5RA protein, human; D053666:Interleukin-5 Receptor alpha Subunit; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D053676:Syntenins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor