Abstract
Inflammation and an influx of macrophages are common elements in many diseases. Among pro-inflammatory cytokines, tumor necrosis factor α (TNFα) plays a central role by amplifying the cytokine network. Progranulin (PGRN) is a growth factor that binds to TNF receptors and interferes with TNFα-mediated signaling. Extracellular PGRN is processed into granulins by proteases released from immune cells. PGRN exerts anti-inflammatory effects, whereas granulins are pro-inflammatory. The factors coordinating these ambivalent functions remain unclear. In our study, we identify Y-box binding protein-1 (YB-1) as a candidate for this immune-modulating activity. Using a yeast-2-hybrid assay with YB-1 protein as bait, clones encoding for progranulin were selected using stringent criteria for strong interaction. We demonstrate that at physiological concentrations, YB-1 interferes with the binding of TNFα to its receptors in a dose-dependent manner using a flow cytometry-based binding assay. We show that YB-1 in combination with progranulin interferes with TNFα-mediated signaling, supporting the functionality with an NF-κB luciferase reporter assay. Together, we show that YB-1 displays immunomodulating functions by affecting the binding of TNFα to its receptors and influencing TNFα-mediated signaling via its interaction with progranulin.
Highlights
Y-box binding protein-1 (YB-1) is a multifunctional protein, which was initially identified by its binding to Y-box motifs within the promoters of human MHC class II genes [1]
In addition to its intracellular functions, YB-1 is secreted via a non-classical pathway following cytokine stimulation with either transforming growth factor β (TGF-β) or platelet-derived growth factor (PDGF) [6,7]
Less is known about extracellular YB-1
Summary
Y-box binding protein-1 (YB-1) is a multifunctional protein, which was initially identified by its binding to Y-box motifs (inverted CCAAT box) within the promoters of human MHC class II genes [1]. Extracellular YB-1 regulates Notch-3 receptor expression and signaling [12]. Tumor necrosis factor α (TNFα) promotes inflammation and tissue-destruction in a number of inflammatory diseases, including glomerulopathies [17,18,19,20,21,22,23,24]. TNF receptor 1 (TNFR1) is widely expressed. Signaling via this receptor promotes pro-inflammatory responses and induces cell death, but it can lead to cell survival [25]. TNF receptor 2 (TNFR2) expression is more restricted. TNFR2 expression is induced on renal cells [26,27,28]. Drug development has more recently focused on interference with cytokine receptors, thereby blocking the activation of cytokine-induced signaling pathways
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