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TWEAK inhibits TRAF2-mediated CD40 signaling by destabilization of CD40 signaling complexes. 2013

Steffen Salzmann, and Isabell Lang, and Alevtina Rosenthal, and Viktoria Schäfer, and Daniela Weisenberger, and José Antonio Carmona Arana, and Johannes Trebing, and Daniela Siegmund, and Manfred Neumann, and Harald Wajant
Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, 97070 Würzburg, Germany.

We found recently that TNF-like weak inducer of apoptosis (TWEAK) and fibroblast growth factor-inducible-14 (Fn14) by virtue of their strong capability to reduce the freely available cytoplasmic pool of TNFR-associated factor (TRAF)2 and cellular inhibitors of apoptosis (cIAPs) antagonize the functions of these molecules in TNFR1 signaling, resulting in sensitization for apoptosis and inhibition of classical NF-κB signaling. In this study, we demonstrate that priming of cells with TWEAK also interferes with activation of the classical NF-κB pathway by CD40. Likewise, there was strong inhibition of CD40 ligand (CD40L)-induced activation of MAPKs in TWEAK-primed cells. FACS analysis and CD40L binding studies revealed unchanged CD40 expression and normal CD40L-CD40 interaction in TWEAK-primed cells. CD40L immunoprecipitates, however, showed severely reduced amounts of CD40 and CD40-associated proteins, indicating impaired formation or reduced stability of CD40L-CD40 signaling complexes. The previously described inhibitory effect of TWEAK on TNFR1 signaling has been traced back to reduced activity of the TNFR1-associated TRAF2-cIAP1/2 ubiquitinase complex and did not affect the stability of the immunoprecipitable TNFR1 receptor complex. Thus, the inhibitory effect of TWEAK on CD40 signaling must be based at least partly on other mechanisms. In line with this, signaling by the CD40-related TRAF2-interacting receptor TNFR2 was also attenuated but still immunoprecipitable in TWEAK-primed cells. Collectively, we show that Fn14 activation by soluble TWEAK impairs CD40L-CD40 signaling complex formation and inhibits CD40 signaling and thus identify the Fn14-TWEAK system as a potential novel regulator of CD40-related cellular functions.

UI MeSH Term Description Entries
D002460 Cell Line Established cell cultures that have the potential to propagate indefinitely. Cell Lines,Line, Cell,Lines, Cell
D005434 Flow Cytometry Technique using an instrument system for making, processing, and displaying one or more measurements on individual cells obtained from a cell suspension. Cells are usually stained with one or more fluorescent dyes specific to cell components of interest, e.g., DNA, and fluorescence of each cell is measured as it rapidly transverses the excitation beam (laser or mercury arc lamp). Fluorescence provides a quantitative measure of various biochemical and biophysical properties of the cell, as well as a basis for cell sorting. Other measurable optical parameters include light absorption and light scattering, the latter being applicable to the measurement of cell size, shape, density, granularity, and stain uptake. Cytofluorometry, Flow,Cytometry, Flow,Flow Microfluorimetry,Fluorescence-Activated Cell Sorting,Microfluorometry, Flow,Cell Sorting, Fluorescence-Activated,Cell Sortings, Fluorescence-Activated,Cytofluorometries, Flow,Cytometries, Flow,Flow Cytofluorometries,Flow Cytofluorometry,Flow Cytometries,Flow Microfluorometries,Flow Microfluorometry,Fluorescence Activated Cell Sorting,Fluorescence-Activated Cell Sortings,Microfluorimetry, Flow,Microfluorometries, Flow,Sorting, Fluorescence-Activated Cell,Sortings, Fluorescence-Activated Cell
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000074049 Cytokine TWEAK A proteolytically-cleaved membrane glycoprotein and member of the TNF superfamily that is highly expressed in a variety of tissues including heart, pancreas, brain, and peripheral blood lymphocytes. The secreted extracellular form is a weak inducer of APOPTOSIS for some cell types and a ligand for the FN14 RECEPTOR. It mediates activation of NF-KAPPA-B and promotes ANGIOGENESIS and proliferation of ENDOTHELIAL CELLS, as well as expression of cytokines involved in INFLAMMATION. Apo3 Ligand,TNF-Related Weak Inducer of Apoptosis,TWEAK Cytokine,Tumor Necrosis Factor Ligand Superfamily Member 12,Cytokine, TWEAK,Ligand, Apo3,TNF Related Weak Inducer of Apoptosis,TWEAK, Cytokine
D000074050 TWEAK Receptor A receptor for TWEAK cytokine that is highly expressed by cells in the heart, placenta, and kidney. It plays a role in ANGIOGENESIS and the proliferation of endothelial cells; it may also modulate cellular adhesion to the extracellular matrix. CD266 Antigen,Fn14 Receptor,Fn14 TWEAK Receptor,TNF Receptor Superfamily Member 12A,TWEAK Receptor Fn14,TWEAKR,Tumor Necrosis Factor Receptor Superfamily, Member 12A,Tumor Necrosis Factor-like Weak Inducer of Apoptosis Receptor,Antigen, CD266,Fn14, TWEAK Receptor,Receptor Fn14, TWEAK,Receptor, Fn14,Receptor, Fn14 TWEAK,Receptor, TWEAK,TWEAK Receptor, Fn14,Tumor Necrosis Factor like Weak Inducer of Apoptosis Receptor
D015153 Blotting, Western Identification of proteins or peptides that have been electrophoretically separated by blot transferring from the electrophoresis gel to strips of nitrocellulose paper, followed by labeling with antibody probes. Immunoblotting, Western,Western Blotting,Western Immunoblotting,Blot, Western,Immunoblot, Western,Western Blot,Western Immunoblot,Blots, Western,Blottings, Western,Immunoblots, Western,Immunoblottings, Western,Western Blots,Western Blottings,Western Immunoblots,Western Immunoblottings
D015398 Signal Transduction The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. Cell Signaling,Receptor-Mediated Signal Transduction,Signal Pathways,Receptor Mediated Signal Transduction,Signal Transduction Pathways,Signal Transduction Systems,Pathway, Signal,Pathway, Signal Transduction,Pathways, Signal,Pathways, Signal Transduction,Receptor-Mediated Signal Transductions,Signal Pathway,Signal Transduction Pathway,Signal Transduction System,Signal Transduction, Receptor-Mediated,Signal Transductions,Signal Transductions, Receptor-Mediated,System, Signal Transduction,Systems, Signal Transduction,Transduction, Signal,Transductions, Signal
D047468 Immunoprecipitation The aggregation of soluble ANTIGENS with ANTIBODIES, alone or with antibody binding factors such as ANTI-ANTIBODIES or STAPHYLOCOCCAL PROTEIN A, into complexes large enough to fall out of solution. Co-Immunoprecipitation,Immune Precipitation,Co Immunoprecipitation,Co-Immunoprecipitations,Immune Precipitations,Precipitation, Immune,Precipitations, Immune
D047992 TNF Receptor-Associated Factor 2 A signal transducing tumor necrosis factor receptor associated factor that is involved in TNF RECEPTOR feedback regulation. It is similar in structure and appears to work in conjunction with TNF RECEPTOR-ASSOCIATED FACTOR 1 to inhibit APOPTOSIS. LMP1-Associated Protein 1,TRAF2,LMP1 Associated Protein 1,TNF Receptor Associated Factor 2
D048069 Tumor Necrosis Factors A family of proteins that were originally identified by their ability to cause NECROSIS of NEOPLASMS. Their necrotic effect on cells is mediated through TUMOR NECROSIS FACTOR RECEPTORS which induce APOPTOSIS. TNF Receptor Ligands,Tumor Necrosis Factor Superfamily Ligands,Necrosis Factors, Tumor,Receptor Ligands, TNF

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