YB-1 acts as a ligand for Notch-3 receptors and modulates receptor activation.
Y-box (YB) protein-1 is secreted by mesangial and immune cells after cytokine challenge, but extracellular functions are unknown. Here, we demonstrate that extracellular YB-1 associates with outer cell membrane components and interacts with extracellular Notch-3 receptor domains. The interaction appears to be specific for Notch-3, as YB-1-green fluorescent protein binds to the extracellular domains and full-length forms of Notch-3 but not to Notch-1. YB-1-green fluorescent protein and Notch-3 proteins co-localize at cell membranes, and extracellular YB-1 activates Notch-3 signaling, resulting in nuclear translocation of the Notch-3 intracellular domain and up-regulation of Notch target genes. The YB-1/Notch-3 interaction may be of particular relevance for inflammatory mesangioproliferative disease, as both proteins co-localize in an experimental nephritis model and receptor activation temporally and spatially correlates with YB-1 expression.
Rauen
Thomas
T
Department of Nephrology and Clinical Immunology, University Hospital RWTH-Aachen, Pauwelsstrasse 30, 52057 Aachen, Germany.
Raffetseder
Ute
U
Frye
Björn C
BC
Djudjaj
Sonja
S
Mühlenberg
Philipp J T
PJ
Eitner
Frank
F
Lendahl
Urban
U
Bernhagen
Jürgen
J
Dooley
Steven
S
Mertens
Peter R
PR
D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D015870:Gene Expression; D015432:Glomerulonephritis, Membranoproliferative / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008024:Ligands; D008297:Male; D051379:Mice; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D049452:Green Fluorescent Proteins; D008024:Ligands; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D014157:Transcription Factors; C499373:Notch3 protein, mouse; C541744:Ybx1 protein, mouse