Interference of the cold shock protein YB-1 and progranulin on tumor necrosis factor-alpha signalling in inflammatory renal disease
Final Report 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. Anti-TNF therapy has proven effective in a number of diseases, including lupus nephritis, however 50% of patients receiving anti-TNF therapy experience treatment failure. Therefore additional approaches are required. Progranulin (PGRN) is a growth factor which binds to TNF receptors and interferes with TNFαmediated 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 identified Y-box binding protein-1 (YB-1) as potential candidate for this immune modulating activity. We demonstrate that at physiological concentrations YB-1 interferes with the binding of TNFα to its receptors in a dose-dependent manner. Using a yeast-2-hybrid assay, we identified an interaction between YB-1 and progranulin. We show that YB-1 in combination with progranulin inhibits TNFα-mediated signaling, supporting the functionality in vitro. Additionally, we identify YB-1 as a component of the TNFR signaling pathway and demonstrate that YB-1 is essential for TNF-induced NF-κB activation. 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. Presently, we are seeking to gain structural insights into the nature of the complex, as this will reveal important information regarding the stoichiometry of the subunits involved, as well as provide the basis for designing new inhibitors. Further, we are investigating where YB-1 fits into the TNFR signaling cascade to determine how YB-1 regulates the activation of NF-κB p65. The further development of this project is being pursued within the application for the research unit: “Cold shock proteins, new targets for diagnostics and therapy”.
Publications
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Differential distribution of Y-box-binding protein 1 and cold shock domain protein A in developing and adult human brain. Brain Struct Funct. 2015;220(4):2235-45
Bernstein HG, Lindquist JA, Keilhoff G, Dobrowolny H, Brandt S, Steiner J, Bogerts B, Mertens PR
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Cold Shock Proteins Mediate GN with Mesangioproliferation. J Am Soc Nephrol. 2016;27(12):3678-3689
Zhu C, Sauter E, Schreiter A, van Roeyen CR, Ostendorf T, Floege J, Gembardt F, Hugo CP, Isermann B, Lindquist JA, Mertens PR
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Early changes in the metabolic profile of activated CD8(+) T cells. BMC Cell Biol. 2016;17(1):28
Cammann C, Rath A, Reichl U, Lingel H, Brunner-Weinzierl M, Simeoni L, Schraven B, Lindquist JA
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Inflammatory cell infiltration and resolution of kidney inflammation is orchestrated by the cold-shock protein Y-box binding protein-1. Kidney Int. 2017;92(5):1157-1177
Bernhardt A, Fehr A, Brandt S, Jerchel S, Ballhause TM, Philipsen L, Stolze S, Geffers R, Weng H, Fischer KD, Isermann B, Brunner-Weinzierl MC, Batra A, Siegmund B, Zhu C, Lindquist JA, Mertens PR
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RSK-mediated nuclear accumulation of the cold-shock Y-box protein-1 controls proliferation of T cells and T-ALL blasts. Cell Death Differ. 2017;24(2):371-383
Gieseler-Halbach S, Meltendorf S, Pierau M, Weinert S, Heidel FH, Fischer T, Handschuh J, Braun-Dullaeus RC, Schrappe M, Lindquist JA, Mertens PR, Thomas U, Brunner-Weinzierl MC
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Cold shock proteins: from cellular mechanisms to pathophysiology and disease. Cell Commun Signal. 2018;16(1):63
Lindquist JA, Mertens PR
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Crosstalk between Akt signaling and cold shock proteins in mediating invasive cell phenotypes. Oncotarget. 2018;9(27):19039-19049
Hohlfeld R, Brandt S, Bernhardt A, Gorny X, Schindele D, Jandrig B, Schostak M, Isermann B, Lindquist JA, Mertens PR
