YB-1 Interferes with TNFα–TNFR Binding and Modulates Progranulin-Mediated Inhibition of TNFα Signaling

Hessman, Christopher L.; Hildebrandt, Josephine; Shah, Aneri; Brandt, Sabine; Bock, Antonia; Frye, Björn C.; Raffetseder, Ute; Geffers, Robert; Brunner-Weinzierl, Monika C.; Isermann, Berend; Mertens, Peter R.; Lindquist, Jonathan A.

doi:10.3390/ijms21197076

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YB-1 Interferes with TNFα–TNFR Binding and Modulates Progranulin-Mediated Inhibition of TNFα Signaling

Christopher L. Hessman

^1,†,

Josephine Hildebrandt

^1,†,

¹,

¹,

^2,‡,

²,

³,

Monika C. Brunner-Weinzierl

⁴,

Berend Isermann

⁵

Peter R. Mertens

^1,* and

Jonathan A. Lindquist

^1,*

Clinic of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke University, 39120 Magdeburg, Germany

Department of Nephrology and Clinical Immunology, RWTH Aachen University, 52074 Aachen, Germany

Genome Analytics Research Group, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany

⁴

Department of Experimental Pediatrics, Otto-von-Guericke University, 39120 Magdeburg, Germany

⁵

Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, 04103 Leipzig, Germany

Authors to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

^‡

Present address: Department of Pneumology, Medical Center–University Hospital Freiburg, 79106 Freiburg, Germany.

Int. J. Mol. Sci. 2020, 21(19), 7076; https://doi.org/10.3390/ijms21197076

Received: 4 September 2020 / Revised: 21 September 2020 / Accepted: 22 September 2020 / Published: 25 September 2020

(This article belongs to the Special Issue Signal Transduction: From Molecular Pathways to Translational Research)

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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. View Full-Text

Keywords: Y-box binding protein-1 (YB-1); DNA binding protein-B (DbpB); progranulin; tumor necrosis factor alpha (TNFα); inflammation; immune modulation; signaling; macrophage

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MDPI and ACS Style

Hessman, C.L.; Hildebrandt, J.; Shah, A.; Brandt, S.; Bock, A.; Frye, B.C.; Raffetseder, U.; Geffers, R.; Brunner-Weinzierl, M.C.; Isermann, B.; Mertens, P.R.; Lindquist, J.A. YB-1 Interferes with TNFα–TNFR Binding and Modulates Progranulin-Mediated Inhibition of TNFα Signaling. Int. J. Mol. Sci. 2020, 21, 7076. https://doi.org/10.3390/ijms21197076

AMA Style

Hessman CL, Hildebrandt J, Shah A, Brandt S, Bock A, Frye BC, Raffetseder U, Geffers R, Brunner-Weinzierl MC, Isermann B, Mertens PR, Lindquist JA. YB-1 Interferes with TNFα–TNFR Binding and Modulates Progranulin-Mediated Inhibition of TNFα Signaling. International Journal of Molecular Sciences. 2020; 21(19):7076. https://doi.org/10.3390/ijms21197076

Chicago/Turabian Style

Hessman, Christopher L., Josephine Hildebrandt, Aneri Shah, Sabine Brandt, Antonia Bock, Björn C. Frye, Ute Raffetseder, Robert Geffers, Monika C. Brunner-Weinzierl, Berend Isermann, Peter R. Mertens, and Jonathan A. Lindquist. 2020. "YB-1 Interferes with TNFα–TNFR Binding and Modulates Progranulin-Mediated Inhibition of TNFα Signaling" International Journal of Molecular Sciences 21, no. 19: 7076. https://doi.org/10.3390/ijms21197076

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YB-1 Interferes with TNFα–TNFR Binding and Modulates Progranulin-Mediated Inhibition of TNFα Signaling

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