YB-1 Interferes with TNF?-TNFR Binding and Modulates Progranulin-Mediated Inhibition of TNF? Signaling.

ABSTRACT: Inflammation and an influx of macrophages are common elements in many diseases. Among pro-inflammatory cytokines, tumor necrosis factor ? (TNF?) plays a central role by amplifying the cytokine network. Progranulin (PGRN) is a growth factor that binds to TNF receptors and interferes with TNF?-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 TNF? 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 TNF?-mediated signaling, supporting the functionality with an NF-?B luciferase reporter assay. Together, we show that YB-1 displays immunomodulating functions by affecting the binding of TNF? to its receptors and influencing TNF?-mediated signaling via its interaction with progranulin.

SUBMITTER: Hessman CL 

PROVIDER: S-EPMC7583764 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature